Table 1.

Recent advances in potential therapeutic approaches targeting non-CMs in cardiac remodeling

Targeted cells	Potential therapy	Species	Disease model	Key observations	Mechanism
Cardiac fibroblasts	NM922 40	mouse	pressure overload-induced cardiac hypertrophy and HF	attenuated LV dilation and hypertrophy, inhibited fibroblast activation	reducing the activation of FAK-Akt-P70S6K and STAT3/E4-BP1 pathway
	LCZ696 41	mouse	left ventricle pressure overload-induced cardiac remodeling	ameliorated pressure overload- induced cardiac fibrosis	restoration of PKG (protein kinase G) signaling
	direct cardiac reprogramming 51	human	-	human adult fibroblasts were reprogrammed into iCMs, along with expression of cardiac markers, and sarcomere-like structures	inducement of cardiac transcription factors and muscle-specific miRNAs
	oleic acid 138	mouse	Ang II-induced cardiac remodeling	prevented Ang II-induced cardiac fibrosis and improved heart function	suppressing the expression of FGF23 (fibroblast growth factor 23)
	DM-celecoxib 139	rat	isoprenaline-induced cardiac remodeling	suppressed cardiac hypertrophy and fibrosis	inhibiting Akt-mediated GSK-3 phosphorylation
	simvastatin 140	human	TGF-β1-induced human ventricular fibroblast differentiation	reduced hVF proliferation and myofibroblast differentiation	activation of protein-phosphatases PPM1A and PP2A interacting with SMAD2/3
	Givinostat 141	mouse	acute myocardial infarction generated by LAD ligation	reduced cardiac fibrosis and improved cardiac performance	targeting endothelial-to-mesenchymal transition (EndMT)
Cardiac macrophages	aminooxyacetic acid 81	mouse	cardiac remodeling after LAD ligation-induced MI	attenuated post-MI cardiac remodeling	balancing M1/M2 macrophage phenotypes and inhibiting NLRP3-Caspase1/IL-1β pathway
	eicosapentaenoic acid 80	mouse	cardiac remodeling after LAD ligation-induced MI	attenuated post-MI cardiac remodeling	inhibiting macrophage polarization toward pro-inflammatory M1 phenotype
	hemin/HA-LP 82	mouse	post-MI cardiac remodeling	improved infarct-related regional function and promoted infarct healing	switching macrophages toward M2 anti-inflammatory phenotype
	dapagliflozin 85	rat	post-MI cardiac remodeling	attenuated cardiac fibrosis	regulating macrophage phenotype through RONS/STAT3-dependent pathway
	pioglitazone-NPs 86	mouse	post-MI cardiac remodeling	attenuated cardiac remodeling	reducing macrophage recruitment and polarizing macrophages towards the pro-healing M2 phenotype
	cardiac stem cell therapy 87	mouse	ischemia-reperfusion injury	enhanced cardiac function	through an acute immune response, characterized by a significant accumulation of CCR2+ and CX3CR1+ macrophages
	transplantation of neonatal cardiac macrophages 88	mouse	post-MI cardiac remodeling	improved MI-injured adult cardiac repair	stimulating the proliferation of CMs
	Qishen Granule 142	rat	cardiac remodeling after LAD ligation-induced MI	attenuated myocardial fibrosis	suppressing the recruitment of monocytes via MCP1/CCR2 pathway, and balancing M1/M2 macrophage phenotypes
	miRNA-21 NPs 143	mouse	cardiac remodeling after LAD ligation-induced MI	reduced hypertrophy, fibrosis and cell apoptosis	specifically targeting macrophages and eliciting their phenotype switch from M1 to reparative M2
Neutrophils	memantine 144	rat	isoproterenol-induced HF	reduced cardiac remodeling and improved cardiac performance	reducing lipid peroxidation and neutrophil infiltration
Lymphocytes	tolerogenic dendritic cells 118	mouse	cardiac remodeling after LAD ligation-induced MI	improved cardiac remodeling, preserved left ventricular systolic function, and improved survival	inducing a systemic activation of MI-specific Treg cells
	CD8+ OT-I T cells 119	mouse	Ang II/PE-induced cardiac fibrosis	attenuated myocardial fibrosis and hypertrophy	directly modifying T cells
	rituximab 145	mouse	pressure overload-induced cardia remodeling	suppressed myocyte hypertrophy, fibrosis and oxidative stress, and improved heart function	inhibiting pro-inflammatory cytokines and Th2 cytokine-mediated IgG production from B cells
Endothelial cells	serelaxin 146	mouse	cardiac fibrosis induced by ascending aortic constriction (AAC) and Ang II infusion	attenuated myocardial fibrosis in both models	preventing EndMT through the endothelial Relaxin family peptide receptor 1
	VEGF nanoparticles 147	mouse	post-MI cardiac remodeling	increased vascular density in the peri-infarct region, and improved the LV contractile function 4 weeks after treatment	promoting neovascularization in the infarcted heart
	VEGF-B gene therapy 148	mouse	doxorubicin-induced cardiomyopathy	reduced whole-body wasting, and improved pathological remodeling,	protecting endothelial cells from apoptosis and restoring their normal function
	VEGFA/S1P-deliveried bone marrow cells 149	mouse	post-MI cardiac remodeling	increased endothelial cells, prevented cardiac fibrogenesis and adverse cardiac remodeling	improving micro-vascularization and oxygen diffusion