Angiopoietin-like protein 7: A narrative review and its potential roles in post-myocardial infarction fibrosis

Summary

Angiopoietin-like protein 7 (ANGPTL7) is a secreted protein involved in tissue remodeling and fibrosis, playing roles in various pathological processes such as glaucoma, metabolic disorders, and cancer. Current research has found that ANGPTL7 plays a role in various diseases, including tumors, metabolic disorders, and glaucoma. In recent years, its potential functions in the cardiovascular system have begun to be preliminarily explored. Research suggests that ANGPTL7 expression levels may be associated with the pathological progression of atherosclerosis and hypertension, and it has shown potential as a prognostic biomarker in acute heart failure. Given its known pro-fibrotic biological functions and emerging links to cardiovascular pathology, this review first comprehensively integrates the molecular mechanisms and functions of ANGPTL7 across various disease contexts, with a primary focus on its roles in the cardiovascular system. Building on this foundation, this review further constructs and explores a comprehensive hypothesis regarding its potential role in pathological fibrosis following myocardial infarction. A deeper understanding of ANGPTL7 could offer a novel therapeutic strategy to mitigate cardiac fibrosis and, ultimately, prevent heart failure.

Graphical abstract

health sciences; medicine; medical specialty; cardiovascular medicine; biological sciences; biochemistry; physiology

Introduction

Angiopoietin-like proteins (ANGPTLs) are a family of pleiotropic secreted proteins that play roles in various physiological and pathological processes.^1,2,3 Among them, ANGPTL7 has been confirmed to participate in the structural and functional remodeling of various tissues.⁴ It was initially identified and extensively studied in ocular tissues, where it influences corneal structure and is associated with the pathology of glaucoma.^4,5 However, its functions are far broader. Subsequent research has revealed its deep involvement in other major pathological processes. For instance, in oncology, ANGPTL7 has been shown to regulate tumor growth and metastasis in various cancers.⁶ In the context of metabolic disorders, it is linked to lipid metabolism and insulin resistance.^7,8 Additionally, studies on skeletal biology have implicated its role in bone and cartilage homeostasis.^9,10,11 It is noteworthy that across these diverse pathological conditions, fibrosis emerges as a common pathological feature significantly associated with ANGPTL7.^12,13,14 Building on this background, the potential role of ANGPTL7 in the cardiovascular system has also begun to attract significant attention in recent years. Preliminary studies suggest its association with the pathogenesis of atherosclerosis and hypertension.¹⁵ Furthermore, its circulating levels have been reported to have prognostic value in patients with acute heart failure (AHF),¹⁶ directly linking it to adverse cardiac outcomes.

Pathological cardiac fibrosis following myocardial infarction (MI) is a fundamental adverse tissue remodeling process that leads to heart failure.^17,18 Given the known role of ANGPTL7 in tissue remodeling and its emerging association with cardiovascular pathology, this review aims to systematically integrate existing literature on the biological functions of ANGPTL7 and explore its potential role in promoting cardiac fibrosis following MI. Additionally, this review will address current research limitations and knowledge gaps, providing a potential theoretical framework for future studies targeting ANGPTL7 as a therapeutic intervention for post-MI fibrosis.

Biological characteristics of ANGPTL7

ANGPTL7, also known as cornea-derived transcript 6, was first discovered in 1998 through molecular cloning techniques from the human cornea.⁵ Its structure is similar to other typical ANGPTL family members (except ANGPTL8), displaying distinct modular characteristics primarily composed of three parts (Figure 1): an N-terminal signal peptide that guides secretion; an N-terminal coiled-coil domain that mediates protein oligomerization; and a C-terminal fibrinogen-like domain (FLD), considered the core of its biological function, which mediates interactions with receptors or extracellular matrix (ECM) components.⁶

Figure 1.

Schematic representation of the structural domains, post-translational modifications, and oligomerization of ANGPTL7

The ANGPTL7 monomer consists of an N-terminal signal peptide, a coiled-coil domain, and a C-terminal FLD. During maturation, the signal peptide is cleaved, and the protein undergoes N-linked glycosylation. Subsequently, mature monomers assemble into higher-order oligomers through interchain disulfide bonds formed via cysteine residues (e.g., cys-53) within the coiled-coil domain. ANGPTL7, angiopoietin-like protein 7; ECM, extracellular matrix; FLD, fibrinogen-like domain. This figure was created by Figdraw (https://www.figdraw.com/).

The maturation process of ANGPTL7 begins with the cleavage of the N-terminal signal peptide, resulting in the formation of a mature monomer. This mature human ANGPTL7 monomer consists of 320 amino acids (Gln27-Pro346), with a predicted molecular weight of approximately 40 kDa.⁶ However, due to post-translational N-linked glycosylation modifications, its apparent molecular weight is significantly increased, typically observed within the range of 45–50 kDa. Subsequently, these mature monomers undergo further assembly. Crucially, cysteine residues located within the coiled-coil domain (such as Cys-53) form interchain disulfide bonds, driving the oligomerization of monomers into higher-order structures. This oligomeric state is a common mode for the ANGPTL family to exert biological activity. For instance, ANGPTL4 inhibits lipoprotein lipase (LPL) activity precisely through its oligomers.¹⁹ For ANGPTL7, oligomerization is hypothesized to be the key to its biological function. This high-order structure not only enhances stability in bodily fluids and tissues, but also, by providing multiple binding sites, it may significantly improve affinity with ECM components or cell surface receptors as well as signaling efficiency. The following chapter will therefore systematically analyze the main molecular mechanisms of ANGPTL7 (Figure 2).

Figure 2.

The core molecular mechanisms of ANGPTL7 in different pathologies

These mechanisms can be broadly categorized as direct pro-fibrotic effects, where ANGPTL7 directly remodels the ECM and activates key fibrotic signaling pathways, including the TGF-β and RhoA/ROCK pathways, leading to cellular stiffening and pathological matrix deposition; indirect pro-fibrotic effects, mediated by its ability to amplify inflammation and oxidative stress. ANGPTL7 activates pro-inflammatory pathways such as p38 MAPK and NF-κB, while also exhibiting a complex, dual immunomodulatory role by binding to the inhibitory receptor LILRB2 on myeloid cells; crosstalk with other key pathways, highlighting its ability to interact with other critical signaling systems such as Wnt/β-catenin, insulin signaling (via SOCS3), and angiogenesis, thereby further influencing cellular behavior and tissue remodeling in a context-dependent manner. ANGPTL7, angiopoietin-like protein 7; Akt, protein kinase B; CLANs, cross-linked actin networks; COX-2, cyclooxygenase-2; ECM, extracellular matrix; eNOS, endothelial nitric oxide synthase; FLD, fibrinogen-like domain; HO-1, heme oxygenase-1; ICAM-1, intercellular adhesion molecule 1; IL-1β, interleukin-1 beta; IL-6, interleukin-6; iNOS, inducible nitric oxide synthase; IRS1, insulin receptor substrate 1; LILRB2, leukocyte immunoglobulin-like receptor B2; MAPK, mitogen-activated protein kinase; MDA, malondialdehyde; MMP1, matrix metallopeptidase 1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NO, nitric oxide; Nrf2, nuclear factor erythroid 2-related factor 2; RhoA, ras homolog family member A; ROCK, Rho-associated, coiled-coil-containing protein kinase; ROS, reactive oxygen species; SOCS3, suppressor of cytokine signaling 3; SP1, specificity protein 1; TGF-β, transforming growth factor-beta; TM, trabecular meshwork; TNF-α, tumor necrosis factor-alpha; VCAM-1, vascular vell adhesion molecule 1. This figure was created by Figdraw (https://www.figdraw.com/).

Mechanistic analysis of ANGPTL7 function

Pro-fibrotic

Fibrosis, a common pathological outcome of chronic injury and inflammation, is characterized by the excessive deposition and structural remodeling of ECM proteins, ultimately leading to tissue scarring and loss of organ function.²⁰ Current research suggests that ANGPTL7 may exert its pro-fibrotic effects by directly remodeling the physical and biochemical properties of the ECM and influencing classical fibrosis-related signaling pathways.

Direct regulation of ECM

ANGPTL7 can directly remodel the proteome of the tissue microenvironment. Under stimulation by glucocorticoids (such as dexamethasone [DEX]) and transforming growth factor β 2 (TGF-β2), ANGPTL7 expression is significantly upregulated (30.3-fold).⁴ Silencing ANGPTL7 reduces DEX-induced ECM gene expression (e.g., fibronectin decreased by 3.4-fold and myocilin decreased by 2.3-fold).⁴ Kuchtey et al. found in trabecular meshwork (TM) cell lines and melanoma cell lines that ANGPTL7 overexpression increases the expression of type I and type V collagen, leading to abnormal vascular morphology and deposit formation.¹²

However, Comes et al. found in primary human TM cells that overexpression of ANGPTL7 downregulated a series of key ECM components, including structural fibronectin and collagen types I, IV, V, as well as myocilin and versican, which are associated with glaucoma pathology.⁴ At the same time, it upregulates the expression of the matrix-degrading enzyme matrix metallopeptidase 1.⁴ This appears to indicate its anti-fibrotic effect. However, in this experiment, ANGPTL7 overexpression increased by 2,188-fold. Such an extreme elevation may trigger feedback mechanisms and does not reflect physiological conditions. On the other hand, research has confirmed that it actively interferes with the normal fibrillar assembly process of fibronectin,⁴ constructing a defective matrix with abnormal biomechanical properties and dysfunctional signaling. This abnormal matrix alone is sufficient to create a vicious cycle in the microenvironment that continuously activates fibroblasts and drives the fibrotic process.

TGF-β signaling axis

TGF-β signaling axis serves as a key knot in the fibrotic process, initiating the cascade of myofibroblast differentiation and ECM synthesis through both canonical Smad-dependent and non-canonical pathways.²¹ ANGPTL7 exhibits a bidirectional interaction with this signaling axis. First, ANGPTL7 is a direct downstream effector molecule of TGF-β signaling. In human TM cells and chondrocytes, TGF-β can effectively induce the expression of ANGPTL7.¹² This suggests that after injury events, such as MI, the large amounts of TGF-β released by cardiomyocytes and immune cells may rapidly upregulate ANGPTL7, enabling it to act as an early responder and amplifier, deeply involved in subsequent tissue repair and fibrosis. Secondly, ANGPTL7 can selectively remodel the signaling output of TGF-β, specifically amplifying its pro-fibrotic effects. The TGF-β signaling pathway exhibits duality and can also exert anti-inflammatory effects under specific circumstances.²² However, ANGPTL7 can specifically antagonize the anti-inflammatory effects of TGF-β1 in macrophages.²³ During the repair phase after MI, timely resolution of inflammation is a prerequisite for preventing excessive fibrosis.²⁴ Thus, by inhibiting the anti-inflammatory effects of TGF-β, ANGPTL7 may lead to the persistence of a pro-inflammatory state, providing a continuous driving force for the subsequent uncontrolled fibrosis.

Ras homolog family member A/Rho-associated, coiled-coil-containing protein kinase signaling pathway

The Ras homolog family member A/Rho-associated, coiled-coil-containing protein kinase (RhoA/ROCK) signaling pathway is widely recognized as a central hub in the fibrotic process, primarily regulating cell tension and contractility through the modulation of the actin cytoskeleton. Its persistent activation across multiple organs is a common hallmark of tissue fibrosis.²⁵ Recent studies have shown that ANGPTL7 plays a role as an upstream activator in RhoA/ROCK pathway in TM cells. The transcription factor specificity protein 1 (SP1) can bind to its promoter region to promote ANGPTL7 expression.²⁶ Upregulated ANGPTL7 activates the RhoA/ROCK signaling pathway. The main effect following the activation of this pathway is the substantial formation of cross-linked actin networks (CLANs) in TM cells.²⁶ CLANs are a highly ordered actin structure whose emergence significantly enhances the internal stiffness of cells.²⁷ This ANGPTL7-mediated alteration in cellular mechanics, characterized by the formation of CLANs, not only directly contributes to increased aqueous humor outflow resistance but also closely mimics the typical pathological features of tissue stiffening during fibrosis.

Although the aforementioned mechanisms provide a preliminary framework for understanding the pro-fibrotic function of ANGPTL7, critical knowledge gaps remain. First, what is the molecular switch for its bidirectional regulation of ECM protein expression levels? At what concentration or cellular state does it shift from promoting collagen synthesis to inhibiting fibronectin expression? Second, is there a hierarchical relationship or crosstalk between these different intracellular signaling pathways (TGF-β vs. RhoA/ROCK)? Most fundamentally, the specific cell surface receptors mediating these direct effects remain the greatest mystery in this field. Only by elucidating these universal mechanistic questions can we further verify their specific manifestations in the particular cell type of cardiac fibroblasts.

Potential indirect fibrogenic effect

In addition to direct effects, current evidence suggests that ANGPTL7 may also indirectly shape a pathological microenvironment conducive to fibrosis by amplifying inflammatory responses and exacerbating oxidative stress—two closely interconnected damage signals.

Pro-oxidative stress

Oxidative stress is the consequence of an imbalance between the production and clearance of reactive oxygen species (ROS) within cells, serving as one of the fundamental mechanisms driving cellular damage and pathological fibrosis.²⁸ ANGPTL7 can directly induce oxidative stress. For instance, overexpression of ANGPTL7 in HepG2 cells activates the STAT3-iNOS-COX-2 pathway, leading to increased levels of ROS and the lipid peroxidation product malondialdehyde, while depleting key antioxidants glutathione and superoxide dismutase.²⁹ In human umbilical vein endothelial cells (HUVECs), ANGPTL7 was identified as a downstream mediator of the pro-inflammatory tumor necrosis factor α (TNF-α) in inducing oxidative stress.¹⁵ The mechanism lies in a dual-hit strategy: simultaneously activating pro-oxidative pathways while inhibiting endogenous antioxidant pathways. On one hand, ANGPTL7 directly triggers a burst of ROS and the robust expression of downstream inflammatory mediators (IL-1β, IL-6, and COX-2) by activating the pro-inflammatory NF-κB signaling pathway. On the other hand, ANGPTL7 also suppresses the primary antioxidant defense system—the Nrf2/HO-1 signaling axis—further weakening the vasoprotective NO/eNOS system.¹⁵ This mechanism has been validated in multiple pathological models. In the chronic intermittent hypoxia-induced vascular injury model, upregulation of ANGPTL7 exacerbated ROS-mediated damage, while its downregulation activated the Nrf2/HO-1 pathway to exert protective effects.³⁰ Similarly, in a hydrostatic pressure model simulating glaucoma, the expression of ANGPTL7 increased in parallel with oxidative stress as well as ROS levels and could be suppressed by the antioxidant β-glucogallin, further indicating a direct correlation between the two.³¹

In summary, ANGPTL7 is an active driver of oxidative stress. It exacerbates cellular damage through a double-hit mechanism—simultaneously activating pro-oxidative pathways such as NF-κB while suppressing key antioxidant defenses like Nrf2. Since this function is triggered by signals such as inflammation and hypoxia, it is not an isolated phenomenon but rather an integral component of pro-fibrotic role. This mechanism can form a vicious cycle with ECM remodeling and inflammatory processes, ultimately driving pathological progression.

Pro-inflammatory

Chronic, low-grade inflammation is the core pathological engine driving the occurrence and progression of tissue fibrosis.²³ NF-κB is a key transcription factor within cells, extensively involved in immune responses, inflammation, and tissue fibrosis processes.^32,33 ANGPTL7 activates the NF-κB pathway in endothelial cells, exacerbating inflammatory responses and the progression of atherosclerosis.¹⁵ Mitogen-activated protein kinases (MAPKs) are pivotal signaling hubs that respond to cytokines, growth factors, and physical stress. Their activity is closely linked to the core pathological processes of fibrosis, including inflammation, cell proliferation, and ECM metabolism.²¹ ANGPTL7 has been confirmed as an effective activator of the MAPK pathway, particularly p38 MAPK.²³ The activated p38 MAPK pathway in macrophages drives a robust pro-inflammatory gene expression program, leading to the substantial synthesis and release of various pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, as well as inflammatory enzymes such as COX-2 and iNOS.²³ Additionally, ANGPTL7 can further enhance the pro-inflammatory environment by antagonizing exogenous (DEX) and endogenous (TGF-β1) anti-inflammatory signals.²³ It is noteworthy that the p38 MAPK signaling pathway can also drive the fibrotic process in fibroblasts,³⁴ and members of the ANGPTL family (such as ANGPTL2) have been reported to promote ECM remodeling in a p38 MAPK-dependent manner.³⁵ Therefore, whether ANGPTL7 exerts a similar direct effect in fibroblasts is a significant research direction that remains to be elucidated.

It is worth noting that ANGPTL7 was identified as a ligand for the leukocyte immunoglobulin-like receptor B2 (LILRB2).³⁶ LILRB2 is an inhibitory receptor expressed on myeloid cells, and its activation typically leads to immune suppression.³⁷ The LILRB2 signaling pathway plays a critical role in mediating immune suppression within the tumor microenvironment.³⁸ Research has shown that using specific antibodies to block the binding of LILRB2 to its ligands (including ANGPTL7) can reprogram M2-type macrophages (which have anti-inflammatory/pro-tumor functions) into pro-inflammatory M1 phenotypes and restore the anti-tumor activity of T cells.³⁹ This finding conversely demonstrates that the interaction between ANGPTL7 and LILRB2 contributes to promoting or maintaining the M2-like inflammatory and immunosuppressive state of macrophages.

Overall, ANGPTL7, as a regulator of inflammation and oxidative stress, presents complex and inherently contradictory effects that raise critical scientific questions demanding resolution. The foremost unknown is the decision-making mechanism behind its dual-directional immune modulation. Specifically, what microenvironmental signals (such as other cytokines, pathogen-associated molecular patterns, etc.) determine whether ANGPTL7 preferentially amplifies inflammation via the MAPK/NF-κB pathway or promotes an M2-like immunosuppressive state through the LILRB2 receptor? Secondly, is there a mutually reinforcing causal relationship or vicious cycle between the inflammation and oxidative stress mediated by ANGPTL7? Addressing these fundamental immunobiological questions is key to predicting its net effect within the dynamically evolving, stage-specific (acute inflammatory phase vs. chronic repair phase) immune microenvironment following MI.

Other related mechanisms

The functional network of ANGPTL7 is far more complex than previously described, and its pro-fibrotic effects may be further enhanced through synergy and crosstalk with multiple key biological processes, including wingless-related integration site (Wnt) signaling, metabolic homeostasis, and angiogenesis.

Wnt/β-catenin is another signaling pathway that plays a critical role in pathological fibrosis,^40,41 exhibiting significant synergistic effects with the TGF-β pathway.^42,43 In human hematopoietic stem/progenitor cells (HSPCs), exogenous ANGPTL7 can upregulate the expression of CXCR4 (associated with cell migration),⁴⁴ HOXB4 (linked to self-renewal),⁴⁵ and downstream targets of the Wnt signaling pathway (such as CCND1, AXIN2, and TCF7). It significantly stimulates the in vitro expansion of human HSPCs and enhances their repopulation activity in xenotransplantation.⁴⁶ Given that the expression of ANGPTL7 itself is regulated by TGF-β, this suggests that ANGPTL7 may be located at the intersection of these two major fibrotic pathways, acting as a molecular switch mediating their synergistic effects.

The regulation of cellular metabolic states by ANGPTL7 may also indirectly influence the fibrotic process. Its mechanism lies in the direct interference with the insulin signaling pathway. Suppressor of cytokine signaling 3 (SOCS3) is a critical negative regulatory protein that recognizes and targets insulin receptor substrate 1 (IRS1), mediating its degradation through the ubiquitin-proteasome pathway.⁴⁷ ANGPTL7 can upregulate the protein level of SOCS3, thereby mediating the degradation of IRS1, which inhibits the phosphorylation of downstream Akt and ultimately leads to insulin resistance at the cellular level.^48,49 Given the extensive crosstalk between the insulin signaling pathway and key pathways involved in inflammation, cellular autophagy, and fibrosis, this function of ANGPTL7 provides another potential indirect route for its involvement in fibrosis regulation.

The regulation of angiogenesis by ANGPTL7, due to its close coupling relationship with fibrosis (fibro-angiogenic coupling), also represents one of its potential pro-fibrotic mechanisms. The effect of ANGPTL7 on angiogenesis exhibits significant context-dependent characteristics. For example, in the cornea, it plays an anti-angiogenic role,⁵⁰ but in bronchopulmonary dysplasia or certain tumor models, it exhibits pro-angiogenic effects.^51,52 This dual regulatory capability suggests that it may indirectly influence fibroblast behavior and matrix remodeling by modulating the vascular network in effected areas.

It must be pointed out that current understanding of the crosstalk between ANGPTL7 and other pathways remains largely in the preliminary exploratory or theoretical deduction stage, involving fundamental scientific questions. For example, what is the direct molecular mechanism by which it activates the Wnt pathway? Does it directly interact with the Wnt signaling complex? In terms of angiogenesis, what exactly is the microenvironmental switch that determines its dual, opposing functions—promoting or inhibiting angiogenesis? Regarding its regulation of insulin signaling, is this an inherent independent function or a downstream consequence of its pro-inflammatory effects?

This intricate network of molecular mechanisms determines that ANGPTL7 may play significant, and sometimes even contradictory, roles in various physiological and pathological processes. Therefore, to fully comprehend its biological significance, we must elevate our perspective from the molecular level to a holistic view. To systematically integrate these findings and clearly link them to the pathophysiology of post-MI fibrosis, we constructed Table 1 and Figure 3. Table 1 summarizes the core molecular pathways of ANGPTL7, the original cellular and disease models used to validate these mechanisms, and, most importantly, delineates their potential target cells in the heart and their specific implications for post-MI fibrosis. The subsequent sections will discuss the role of ANGPTL7 in non-cardiovascular (Table 1) and cardiovascular contexts (Figure 3) based on this mechanistic framework.

Table 1.

Molecular mechanisms of ANGPTL7 and their potential target cells in the pathophysiology of post-MI fibrosis

Mechanism classification	Molecular pathway	Cell model	Disease model	Corresponding potential target cells in the heart	Pathophysiological significance in post-MI fibrosis	Reference
IDirect profibrosis	RhoA/ROCK	human TM cells	glaucoma	cardiac fibroblasts	→ myofibroblast differentiation → increased cell contractility and increased tissue stiffness → progression of heart failure	Knipe et al.25; Sun et al.26; Bermudez et al.27
	ECM remodeling (collagen and fibronectin)	trabecular meshwork/melanoma cells	glaucoma, tumor	cardiac fibroblasts	collagen quantity ↑ and fibronectin network disruption → dysfunctional scar	Comes et al.4; Peek et al.6; Kuchtey et al.12
	TGF-β signaling integration	human TM cells, chondrocytes, and macrophages	fibrotic diseases	cardiac fibroblasts, macrophages	as a downstream effector molecule → amplifies pro-fibrotic/pro-inflammatory signals → exacerbates fibrosis	Kirkwood et al.13
IIIndirect pro-fibrosis	pro-inflammatory response (MAPK, NF-κB, etc.)	RAW264.7, HUVECs	inflammation, atherosclerosis	macrophages, endothelial cells	enhanced local inflammation → continuous stimulation of fibroblasts → excessive activation	Li et al.15; Qian et al.23
	immunoregulation (LILRB2)	myeloid/leukemia cells	tumor, leukemia	myeloid immune cells (macrophages)	maintaining a pro-fibrotic M2 environment → promotes scar formation and tissue remodeling	Zheng et al.36; Chen et al.38; Niu et al.39
	pro-oxidative stress (NF-κB and Nrf2)	HUVECs and HepG2	chronic hypoxia, vascular injury	myocardial/fibroblast/endothelial cells	ischemia-reperfusion injury ↑ → cell damage and activation of pro-fibrotic signaling	Li et al.15; Gao et al.29; Hypopnea Syndrome30
IIIChannel crosstalk	Wnt/β-catenin	artificial blood stem/progenitor cells	–	cardiac fibroblasts	integrating TGF-β and Wnt signaling → amplifies pro-fibrotic signaling	Akhmetshina et al.42; Yousefi et al.43; Xiao et al.46
	insulin resistance (SOCS3, Akt)	–	T2DM	myocardial/fibroblast	impairing myocardial energy metabolism → indirectly regulating fibroblast function	Xu et al.48; Taheri et al.49

ANGPTL7, angiopoietin-like protein 7; Akt, protein kinase B; ECM, extracellular matrix; HUVECs, human umbilical vein endothelial cells; LILRB2, leukocyte immunoglobulin-like receptor B2; MAPK, mitogen-activated protein kinase; MI, myocardial infarction; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor erythroid 2-related factor 2; RhoA, Ras homolog gene family, member A; ROCK, Rho-associated coiled-coil containing protein kinase; SOCS3, suppressor of cytokine signaling 3; T2DM, type 2 diabetes mellitus; TGF-β, transforming growth factor-beta; TM, trabecular meshwork; Wnt, wingless-related integration site.

Figure 3.

The involvement of ANGPTL7 in the pathogenesis of cardiovascular diseases

In atherosclerosis, ANGPTL7 acts as an amplifier of vascular inflammation and endothelial dysfunction by inducing oxidative stress and upregulating adhesion molecules (e.g., ICAM-1 and VCAM-1). It is also implicated in regulating adaptive immune responses and has been linked to ferroptosis within atherosclerotic plaques. In hypertension, ANGPTL7 is a downstream effector of AngII. The AngII-ANGPTL7 axis promotes VSMC proliferation and inflammation, contributing to pathological vascular remodeling and increased arterial stiffness. In heart failure, elevated circulating levels of ANGPTL7 have been identified as a strong and independent prognostic biomarker for short-term mortality in patients with AHF, likely reflecting its active involvement in adverse myocardial remodeling through its pro-fibrotic and pro-inflammatory functions.AHF, acute heart failure; AngII, angiotensin II; ANGPTL7, angiopoietin-like protein 7; ICAM-1, intercellular adhesion molecule 1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NT-proBNP, N-terminal pro-B-type natriuretic peptide; VCAM-1, vascular cell adhesion molecule 1; VSMCs, vascular smooth muscle cells. This figure was created by Figdraw (https://www.figdraw.com/).

The role of ANGPTL7 in diseases

Tumor

In tumors, the role of ANGPTL7 is dependent on the microenvironment. Its regulation of tumor angiogenesis exhibits duality: in colorectal cancer (CRC) models, it can be hypoxia-induced and delivered via exosomes, exerting pro-angiogenic effects⁵¹; however, in certain xenograft tumor models, overexpression of ANGPTL7 instead suppresses abnormal angiogenesis by inducing fibrosis.⁶ Moreover, Lim et al. found that it is significantly downregulated in CRC liver metastases.⁵³ Myeloid cells (Cd11b⁺) promote CRC liver metastasis by downregulating ANGPTL7 expression. Overexpression of ANGPTL7 significantly reduces liver metastasis and angiogenesis.

On the other hand, other factors can remodel the metastatic niche. For example, in breast cancer, it creates a metastatic portal for tumor cells by increasing vascular permeability⁵⁴; in acute myeloid leukemia, as a key paracrine factor secreted by the bone marrow microenvironment, it is upregulated through a complex signaling cascade involving BMP6-ID1-SP1, which in turn supports the survival and proliferation of tumor cells.⁵⁵

Metabolic diseases

In type 2 diabetes mellitus (T2DM), circulating levels of ANGPTL7 are significantly elevated.⁴⁸ Its pathological contribution lies in its involvement in and amplification of the inflammation-ANGPTL7-insulin resistance vicious cycle. The mechanism involves two aspects. First, it inherently possesses pro-inflammatory effects, exacerbating chronic inflammation triggered by factors such as obesity.^7,8 Second, it directly interferes with insulin signaling pathways by upregulating SOCS3 and inhibiting Akt phosphorylation, thereby worsening insulin resistance.⁴⁸

The level of ANGPTL7 is significantly elevated in obese individuals and is closely associated with hypertriglyceridemia. The underlying mechanism may involve the regulation of LPL.^7,56 Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome and is closely associated with obesity and T2DM. Given the role of ANGPTL7 in the latter two conditions, its function in NAFLD has also begun to attract attention,⁵⁷ although its specific mechanisms remain incompletely understood.

Obstructive sleep apnea (OSA) is a chronic inflammatory disease highly associated with obesity and cardiovascular risks.⁵⁸ Circulating ANGPTL7 levels were significantly elevated in OSA patients and positively correlated with the severity of OSA as well as inflammatory markers (such as triglycerides and oxidized low-density lipoprotein).⁵⁹ Even more compelling is the observation that after undergoing bariatric surgery, patients experienced an improvement in their OSA symptoms, accompanied by a significant decrease in their ANGPTL7 levels.⁵⁹

Eye

In the classic research model of glaucoma, the core pathological function of ANGPTL7 is to drive fibrosis in the trabecular meshwork. This function is achieved through a dual mechanism involving both intra- (cellular) and extra- (matrix) cellular processes: intracellularly, it activates the RhoA/ROCK pathway, leading to cellular stiffness²⁶; Extracellularly, it disrupts the functional structure of the ECM by interfering with the normal network assembly of fibronectin, ultimately increasing the resistance to aqueous humor outflow (as explained in direct regulation of ECM section). Meanwhile, under the physiological conditions of the cornea, it may exert its anti-angiogenic function by promoting the synthesis of type I collagen.^{12,50,60,61,62,63}

Bone and cartilage

During bone formation, ANGPTL7 can directly instruct matrix-generating cells through activating the canonical BMP signaling pathway, upregulating transcription factors such as Runx2, and ultimately promoting the extensive synthesis and mineralization of type I collagen.⁶⁴ In osteoarthritis, a specific subset of chondrocytes with high expression of ANGPTL7 has been identified as the potential initiator driving pathological angiogenesis (H-type vessels) and abnormal remodeling of subchondral bone through the FGF2-FGFR2 signaling pathway.^9,10,11

From fundamental molecular mechanisms to multisystem clinical pathologies, the collective evidence points to ANGPTL7 as a regulator of adverse tissue remodeling and fibrosis. Thus, these findings provide a potential and theoretical foundation for the central hypothesis of this review: ANGPTL7 may be a potential driver of fibrosis following MI. Building upon this integrated body of evidence, the next part will construct and elaborate on this hypothesis in detail.

In cardiovascular diseases

Atherosclerosis

Atherosclerosis is a disease characterized by chronic inflammation of the blood vessel walls and lipid accumulation, serving as the underlying cause of ischemic heart disease.⁶⁵ Recent evidence indicates that ANGPTL7 is involved in multiple key aspects of its pathogenesis. First, ANGPTL7 acts as an amplifier of vascular endothelial dysfunction and inflammation. In the initial stages of atherosclerosis, as a mediator downstream of the pro-inflammatory factor TNF-α, it induces oxidative stress in HUVECs and upregulates the expression of adhesion molecules such as ICAM-1 and VCAM-1, thereby promoting the recruitment and adhesion of leukocytes.¹⁵ Furthermore, its expression level is positively correlated with the infiltration of follicular helper T cells (Tfh cells) in the lesions, suggesting that it also plays a significant role in regulating adaptive immune responses within the plaques.⁶⁶

Ferroptosis is an iron-dependent form of programmed cell death characterized by lipid peroxidation, which is considered closely associated with the death of intraplaque macrophages and smooth muscle cells, as well as plaque instability.⁶⁷ More notably, ANGPTL7 has been identified as a differentially expressed ferroptosis-related gene in coronary atherosclerotic tissues,⁶⁶ providing a novel mechanistic perspective for understanding the pathology of atherosclerosis—its association with ferroptosis.

However, we need to recognize the gaps in research regarding whether and how ANGPTL7 directly regulates the ferroptosis process in macrophages or smooth muscle cells within plaques, as well as its specific molecular pathways in modulating adaptive immune responses such as Tfh cells. These limitations hinder our comprehensive understanding of its role in chronic inflammation within plaques.

Hypertension

High expression of ANGPTL7 was observed in patients with hypertension.⁶⁸ Angiotensin II (AngII) is a key mediator of hypertension, which promotes the cellular viability of vascular smooth muscle cells (VSMCs) and increases the expression of ANGPTL7.⁶⁸ Downregulation of ANGPTL7 expression in AngII-treated VSMCs can inhibit AngII-induced cell proliferation and inflammation, and promote apoptosis.⁶⁸ The proliferation and inflammation of VSMCs driven by the AngII-ANGPTL7 axis serve as the cytological basis for vascular wall thickening and increased stiffness. This process is pathologically defined as pathological vascular remodeling, suggesting ANGPTL7 may be involved in driving fibrotic processes within vascular tissues.

Although ANGPTL7 has been confirmed as a downstream effector molecule of AngII, its upstream regulatory network extends far beyond this. In hypertensive patients, besides AngII, what other pathological factors (such as mechanical stretch, mineralocorticoids, etc.) can induce the expression of ANGPTL7 in VSMCs? More importantly, when ANGPTL7 mediates vascular fibrosis, what are its direct downstream targets or receptors? This is key to developing it as a target for anti-vascular remodeling.

Heart failure

ANGPTL7 was demonstrated to be significant potential as a prognostic biomarker in AHF. Clinical studies have found that serum ANGPTL7 level is a strong and independent predictor of short-term (30 and 90 days) all-cause mortality in AHF patients, and its predictive value remains significant after adjusting for traditional risk factors including NT-proBNP.¹⁶ This prognostic association likely stems from active involvement of ANGPTL7 in the core pathological mechanisms of heart failure. Its observed functions in ECM remodeling and inflammation regulation (as previously mentioned) closely align with the adverse myocardial remodeling phenomena observed during AHF.

However, is the high level of ANGPTL7 in the serum a result of a passive release following massive cardiomyocyte death, or is it due to an increased active secretion by damaged myocardium (or infiltrating immune cells) in response to the injury? This raises a scientific question: in AHF, does the elevated circulating ANGPTL7 level merely serve as a biomarker reflecting myocardial injury severity, or does it act as an active driver promoting cardiac dysfunction and maladaptive remodeling? Given its known biological functions, the latter possibility warrants in-depth investigation.

Hypothesis: The potential role of ANGPTL7 in post-MI fibrosis

Fibrotic microenvironment after MI

Post-MI wound-healing is a complex process centered on cardiac fibrosis, which is essentially characterized by the excessive activation of cardiac fibroblasts and pathological deposition of ECM.²⁰ This ultimately leads to myocardial stiffness, impaired function, and progression toward heart failure.⁶⁹ Among these, cardiac fibroblasts are the primary effector cells, while immune cells such as macrophages serve as the key regulatory hubs.⁶⁹ The core signaling pathways regulating this network include the classical TGF-β/Smad pathway, the stress- and inflammation-mediated MAPK pathway, and the Wnt/β-catenin pathway associated with development and pathological remodeling.^69,70 Any molecule capable of interfering with these cells or signaling pathways may influence the outcome of cardiac remodeling after MI.

Against this background, ANGPTL7 has emerged as a novel regulatory factor of interest. Particularly in patients with AHF, its identification as an independent prognostic marker underscores its direct relevance to cardiac pathology.⁶⁸ However, its direct causal role and specific molecular mechanisms in the particular pathological process following MI remain a critical knowledge gap in the field that urgently needs to be elucidated. Therefore, this chapter aims to integrate existing evidence and systematically propose a multidimensional mechanistic hypothesis regarding the potential role of ANGPTL7 in post-MI fibrosis.

Potential multifaceted regulatory mechanisms of ANGPTL7 in cardiac fibrosis

We speculate that ANGPTL7 is involved in and may exacerbate adverse cardiac remodeling after MI through at least three interrelated mechanisms. First, the intense inflammatory response following MI is the initiating and persistent driving force behind fibrosis.⁷¹ The preceding text has detailed the significant role of ANGPTL7 in inflammatory responses. It can induce a pro-inflammatory phenotype in macrophages by activating the p38 MAPK pathway and amplify the pro-inflammatory effects of cytokines such as TNF-α. Additionally, it antagonizes some of the anti-inflammatory effects of TGF-β1 in macrophages, thereby maintaining the microenvironment in a sustained pro-inflammatory state.²³ Second, as a direct remodeler of the ECM. As previously mentioned, ANGPTL7 can directly regulate the “quality” and “quantity” of the cardiac ECM. Its disruptive effect on the functional assembly of fibronectin in glaucoma models provides a direct mechanistic analogy for understanding how it contributes to poor-quality scarring.⁴ Additionally, its role in promoting type I collagen synthesis via the BMP pathway during bone formation reveals its potential to drive excessive matrix deposition.⁶⁴ Although direct binding analysis data between ANGPTL7 and specific cardiac collagens or fibronectin are currently lacking, its functions suggest the possibility of such interactions. Finally, the significance of ANGPTL7 lies even more in its unique role as an integrative node for multiple core fibrotic pathways. Positioned at the intersection of signaling networks such as TGF-β, Wnt, and MAPK (as previously described), this characteristic enables it to integrate and amplify pro-fibrotic signals from different cells and stages.

In summary, ANGPTL7 may actively participate in the post-MI fibrosis process by amplifying local inflammation, directly affecting ECM homeostasis, and integrating multiple key pro-fibrotic signaling pathways. To systematically validate and refine this theoretical framework and ultimately advance it toward clinical application, future research may need to focus on addressing the following scientific issues: (1) assessing the causal effects of its deficiency or overexpression on cardiac fibrosis, ventricular remodeling, and cardiac function; (2) identifying the primary cellular sources of ANGPTL7 secretion in the heart post-MI and characterizing its specific receptors on key cells such as cardiac fibroblasts and macrophages; (3) elucidating the precise molecular mechanisms of its crosstalk with signaling pathways such as TGF-β, Wnt, and MAPK in the cardiac context, and clarifying its direct impact on collagen and fibronectin synthesis and assembly; and (4) detailed spatiotemporal expression profiles: precisely mapping the expression patterns of ANGPTL7 across different cardiac compartments and cell types, as well as at various stages of MI (e.g., early vs. late MI).

To systematically validate and refine this theoretical framework, we propose the following multi-level experimental strategy. First, at the animal level, establishing ANGPTL7 gene knockout and cardiac-specific overexpression mouse models, and performing MI surgery are crucial for validating their causal relationship. By conducting echocardiography and histological analyses (such as Masson’s staining) at different time points after surgery (e.g., 1 and 4 weeks), the ultimate effects of ANGPTL7 deficiency or overexpression on cardiac function and fibrotic remodeling can be clearly determined. Second, at the cellular level, primary cardiac fibroblasts can be utilized to directly assess the effects of exogenous recombinant ANGPTL7 protein on cell proliferation, migration, and collagen synthesis (e.g., by detecting COL1A1/3 via western blot) to validate its role as a direct ECM remodeler. Concurrently, bone marrow-derived macrophages can be employed to investigate whether ANGPTL7 regulates their polarization toward the M1 pro-inflammatory phenotype through the p38 MAPK pathway. Finally, in terms of mechanism exploration, mass spectrometry-based proteomics can be employed to map the secretome atlas of cells (particularly fibroblasts) stimulated by ANGPTL7, thereby identifying key downstream effectors mediating intercellular paracrine communication. Additionally, the synergistic application of single-cell and spatial transcriptomics will be central. This combined paradigm enables the precise anchoring of cellular heterogeneity, as identified by scRNA-sequencing, back to the original spatial coordinates within cardiac tissue. The core objective is to reconstruct the cellular society of different regions (such as the border zone and remote zone) post-MI in a spatially resolved manner, and to identify paracrine signaling hubs centered around ANGPTL7 expression along with their downstream responsive cell populations. These experiments will systematically address existing knowledge gaps and provide a solid experimental foundation for potential therapeutic strategies targeting ANGPTL7.

Conclusion

This review synthesizes existing evidence and analytical insights regarding the multifaceted biological functions of ANGPTL7, a protein recurrently implicated in tissue remodeling and fibrosis across diverse pathological contexts. Building upon these observations, particularly its established association with adverse cardiovascular outcomes, we propose a hypothesis: ANGPTL7 may act as an active participant in the pathological fibrotic progression following MI. Currently, in addition to the need for further research in the field of post-MI fibrosis (as discussed in the previous section), this field faces several potential scientific challenges: first, the identity of its cell surface receptor remains unresolved, which is the primary obstacle in understanding its functional specificity and developing targeted drugs. Second, the molecular switch mechanism behind contradictory functions in different tissue microenvironments (e.g., inhibiting angiogenesis in the eye while promoting it in tumors) remains unclear. Future research must focus on using unbiased high-throughput screening to identify its receptor, employing specific gene-knockout animal models and single-cell sequencing technologies to elucidate its precise mechanism in cardiac fibrosis and conducting clinical cohort studies to validate its value as a biomarker.

Despite these gaps in knowledge, ANGPTL7 is still an attractive therapeutic target.⁷² A deeper elucidation of ANGPTL7 will not only greatly enhance our understanding of the fundamental mechanisms of tissue fibrosis but also holds promise for transforming this challenging yet opportune molecule into a viable and precise therapeutic target. This could pave the way for novel approaches in preventing and treating major cardiovascular diseases.

Acknowledgments

This work was supported by CAMS Innovation Fund for Medical Science (grant no. 2021-I2M-1-008). The figures and graphical abstract were created by Figdraw (https://www.figdraw.com/).

Author contributions

K.D., Y.S., and X.C. designed the review; X.C. searched for literature and wrote the manuscript; K.D., Y.S., G.L., Z.Z., and R.F. edited and revised the manuscript. All authors have read and approved the article and agree with the publication in this journal.

Declaration of interests

The authors report no conflicts of interest in this work.