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. 2023 Oct 5;56(12):663–668. doi: 10.5483/BMBRep.2023-0127

C-reactive protein accelerates DRP1-mediated mitochondrial fission by modulating ERK1/2-YAP signaling in cardiomyocytes

Suyeon Jin 1,2,#, Chan Joo Lee 1,#, Gibbeum Lim 1, Sungha Park 1, Sang-Hak Lee 1, Ji Hyung Chung 3, Jaewon Oh 1,*, Seok-Min Kang 1,*
PMCID: PMC10761750  PMID: 37817437

Abstract

C-reactive protein (CRP) is an inflammatory marker and risk factor for atherosclerosis and cardiovascular diseases. However, the mechanism through which CRP induces myocardial damage remains unclear. This study aimed to determine how CRP damages cardiomyocytes via the change of mitochondrial dynamics and whether survivin, an anti-apoptotic protein, exerts a cardioprotective effect in this process. We treated H9c2 cardiomyocytes with CRP and found increased intracellular ROS production and shortened mitochondrial length. CRP treatment phosphorylated ERK1/2 and promoted increased expression, phosphorylation, and translocation of DRP1, a mitochondrial fission-related protein, from the cytoplasm to the mitochondria. The expression of mitophagy proteins PINK1 and PARK2 was also increased by CRP. YAP, a transcriptional regulator of PINK1 and PARK2, was also increased by CRP. Knockdown of YAP prevented CRP-induced increases in DRP1, PINK1, and PARK2. Furthermore, CRP-induced changes in the expression of DRP1 and increases in YAP, PINK1, and PARK2 were inhibited by ERK1/2 inhibition, suggesting that ERK1/2 signaling is involved in CRP-induced mitochondrial fission. We treated H9c2 cardiomyocytes with a recombinant TAT-survivin protein before CRP treatment, which reduced CRP-induced ROS accumulation and reduced mitochondrial fission. CRP-induced activation of ERK1/2 and increases in the expression and activity of YAP and its downstream mitochondrial proteins were inhibited by TAT-survivin. This study shows that mitochondrial fission occurs during CRP-induced cardiomyocyte damage and that the ERK1/2-YAP axis is involved in this process, and identifies that survivin alters these mechanisms to prevent CRP-induced mitochondrial damage.

Keywords: C-reactive protein, Cardiomyocyte, DRP1, Mitochondria, Survivin

INTRODUCTION

C-reactive protein (CRP), a pentameric molecule present in the serum, which is a well-known inflammatory response marker, is a risk factor for cardiovascular disease (1). Elevated plasma CRP levels are associated with an increased risk of atherothrombotic events, myocardial infarction, and heart failure (2-4). In addition to being a prognostic factor, CRP is a cell-damaging substance. Many experimental studies have reported that CRP inhibits endothelial progenitor cell differentiation, promotes pressure overload-induced cardiac remodeling, and accelerates hypoxia-mediated apoptosis in neonatal cardiomyocytes (5-7).

The heart is the most metabolically active organ in the mammalian body. Therefore, energy metabolism in cardiomyocytes is crucial. Cardiomyocytes generate over 90% of their ATP from mitochondria; hence, mitochondrial dysfunction is a key mechanism that causes cardiovascular diseases, such as heart failure (8). Maintaining healthy mitochondria is essential for normal cell function and survival of cardiomyocytes (9). Mitochondria are dynamic organelles that balance fission and fusion in healthy cells (10). When they are damaged, they are biased towards fusion to repair the damage, whereas in irreversible damage, they are biased towards fission (11). These mitochondrial dynamics are essential mechanisms in the mitochondrial response to damage. Mitophagy is an autophagic response that removes damaged and dysfunctional mitochondria that can be harmful to cells. It is an important mechanism for maintaining a healthy mitochondrial population for normal cell function and survival (9).

Although mitochondrial dynamics and mitophagy are critical biological phenomena, studies on their roles in CRP-induced cardiomyocyte injury are limited. CRP induces mitochondrial dysfunction by accumulating mitochondrial reactive oxygen species (mtROS) in coronary artery endothelial cells (12). Therefore, we hypothesized that CRP induces cardiotoxicity by modulating mitochondrial dynamics and mitophagy in cardiomyocytes.

Survivin, a member of the inhibitor of apoptosis protein (IAP) family, participates in cell survival and oncogenesis (13). CRP is known to reduce survivin expression in cardiomyocytes (14), and we previously showed that survivin has a cytoprotective effect against doxorubicin-induced cardiotoxicity (15). However, the effects of survivin on CRP-induced cardiomyocyte injury, particularly mitochondrial damage, have not been studied. Therefore, this study aimed to determine how mitochondrial dynamics are involved in CRP-induced cardiomyocyte damage and whether survivin exerts a cardioprotective effect in this process.

RESULTS

CRP induces mitochondrial fragmentation in H9c2 cardiomyocytes

To investigate the effect of CRP on mitochondrial dynamics, H9c2 cardiomyocytes were treated with 50 μg/ml CRP for 24 h, and morphological changes were observed using MitoTracker Green FM live cell staining (Fig. 1A). The mitochondrial lengths were significantly shortened by CRP, indicating that CRP induced mitochondrial fragmentation. Fluorescence microscopy revealed more intracellular MitoSOX Red accumulation in CRP-treated cells than in control-treated cells (Fig. 1B). Using CM-H2DCFDA, another ROS production indicator, ROS production significantly increased with time in CRP-treated, revealing that CRP caused a significant increase in mitochondrial ROS production in H9c2 cells (Fig. 1C).

Fig. 1.

Fig. 1

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Effect of CRP on mitochondrial morphology and relative gene and protein expression levels in H9c2 cardiomyocytes. H9c2 cardiomyocytes were treated with CRP (50 μg/ml) for 24 h. (A) Mitochondrial morphology (green) in live cells was visualized using Hoechst (blue) and MitoTracker Green FM. Mitochondrial lengths were quantified using Image J software. (B) Mitochondria that produce mitochondrial superoxide (red) were visualized with MitoSOX Red and Hoechst (blue). (C) Time-dependent accumulation of mtROS was measured using CM-H2DCFDA. The expression levels of the related genes and proteins were verified using RT-PCR and immunoblot assays. (D) Total RNA was purified and analyzed with RT-PCR using specific primers associated with mitochondrial morphology. (E) Protein levels in whole cell lysates were evaluated through immunoblotting. Data represent the mean of at least five independent experiments. Scale bar: 5 μm. *P < 0.05, **P < 0.01, ***P < 0.001.

To identify the mechanism by which CRP influences mitochondrial dynamics, we used reverse transcription-polymerase chain reaction (RT-PCR) and western blot to investigate whether CRP regulated the expression of genes and proteins involved in mitochondrial fission and fusion. CRP treatment increased the mRNA and protein levels of dynamin-related protein 1 (DRP1), which is involved in mitochondrial fission (Fig. 1D, E). In contrast, the mRNA and protein levels of MFN1, MFN2, and OPA1, which are involved in mitochondrial fusion, were not altered by CRP treatment (Fig. 1D, E).

ERK1/2 is a regulator of DRP1 for mitochondrial fragmentation by CRP treatment

To determine the location of the increase in DRP1 by CRP, we performed immunochemical staining for Tom20, a mitochondrial outer membrane marker, and DRP1. Immunofluorescence microscopy revealed that CRP treatment increased the fluorescence signal of DRP1, which was mainly observed inside the mitochondria rather than in the cytosol (Fig. 2A). Western blotting of the subcellular fractions also revealed an increase in DRP1 protein levels in the mitochondria rather than in the cytosol (Fig. 2B). Therefore, these results suggest that CRP increases DRP1 expression and induces DRP1 translocation from the cytosol to mitochondria.

Fig. 2.

Fig. 2

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Regulation of CRP-induced mitochondrial fragmentation depends on ERK1/2 phosphorylation. To determine DRP1 translocation, cells were treated with CRP for 6 h, after which the following experiments were performed: (A) Confocal immunofluorescence analysis of DRP1 (red) and Tom20 (green) visualized the mitochondrial translocation of DRP1. Scale bar: 5 μm. (B) DRP1 protein levels in cytosolic and mitochondrial fractions were quantified using GAPDH and VDAC1, respectively. (C) H9c2 cardiomyocytes were pretreated with ERK1/2 inhibitor U0126 (5 μM) to verify the ERK1/2-mediated DRP1 expression. Immunoblotting of whole cell lysates showed the total and phosphorylated forms of ERK1/2 and DRP1 expression. (D) Cytosolic and mitochondrial fractions were prepared, and protein levels were compared with or without U0126 treatment. Data represent the mean of at least five independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001.

Our previous study showed that CRP activates ERK1/2, a mitogen-activated protein kinase (MAPK), in H9c2 cardiomyocytes. Reportedly, ERK1/2 phosphorylation at Tyr204 (p-ERK1/2) could promote DRP1-mediated mitochondrial fragmentation (16, 17). Therefore, we hypothesized that CRP-induced mitochondrial fission depended on the activation of ERK-DRP1 signaling. To examine whether the increase in DRP1 expression by CRP was related to ERK1/2 phosphorylation, we pretreated cells with 5 μM U0126 (an ERK1/2 inhibitor) 1 h before CRP treatment. The increase in DRP1 and its phosphorylation at Ser616 (p-DRP1) by CRP were suppressed in U0126-pretreated cells (Fig. 2C). U0126 pretreatment reduced the CRP-induced increase in DRP1 expression in the mitochondrial fractions (Fig. 2D). These results suggest that ERK1/2-DRP1 signaling may regulate CRP-induced mitochondrial fission in H9c2 cardiomyocytes.

YAP regulates DRP1-dependent mitochondrial fragmentation and PINK1/PARK2-induced mitophagy

After DRP1 breaks down damaged mitochondria, the segmented mitochondria undergo degradation through a mitochondrial-specific autophagy process called mitophagy. PTEN-induced putative protein kinase 1 (PINK1) and E3 ubiquitin-protein ligase (PARK2) are essential proteins for mitophagy, and their mutations may augment defective mitochondria (18). Western blotting showed that CRP treatment induced ERK1/2 phosphorylation and increased PINK1 and PARK2 protein expression. U0126 inhibited ERK1/2 phosphorylation and reduced the CRP-induced expression of PINK1 and PARK2 (Fig. 3A).

Fig. 3.

Fig. 3

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Effect of CRP on mitochondrial dynamics-related proteins regulated by ERK1/2-YAP signaling in H9c2 cardiomyocytes. H9c2 cardiomyocytes were pretreated with U0126 (5 μM) for 1 h before CRP treatment. (A) Expression levels of mitophagy-related proteins were quantified through immunoblotting. (B) To determine whether YAP mediated ERK1/2-regulated mitochondrial damage, immunoblotting was performed to determine the protein levels of YAP and TAZ. (C) Cells were transfected with siYAP (30 nM) for 4 h to determine whether YAP contributed to the changes in protein expression levels, and YAP deletion was confirmed via RT-PCR. (D) Expression of DRP1, PINK1, and PARK2 was detected through immunoblotting using each antibody, comparing with and without YAP knockdown. Data represent the mean of at least five independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001.

PARK2 is a major target gene of the Hippo-YAP/TAZ pathway (19). We investigated the changes in YAP/TAZ expression induced by CRP and ERK1/2 inhibition. CRP treatment increased YAP and TAZ protein expression, which was blocked by ERK1/2 inhibition (Fig. 3B). We transfected H9c2 cells with YAP small interfering RNA (siRNA) to confirm whether the CRP-induced changes in DRP1, PINK1, and PARK2 expression were affected by YAP (Fig. 3C). We found that YAP knockdown markedly attenuated these protein expression levels (Fid. 3D), but transfection with TAZ siRNA did not cause a significant increase (Supplementary Fig. 1A, B). This suggests that CRP-induced changes in YAP expression regulate CRP-induced changes in the expression of mitochondrial fission-related proteins.

Survivin, a mitochondrial protein, attenuates CRP-induced mitochondrial damage in H9c2 cardiomyocytes

We previously showed that survivin expression was diminished in CRP-treated cardiomyocytes (14). Hence, we hypothesized that CRP-induced mitochondrial fission would restore survivin levels. We previously manufactured a recombinant survivin protein using the His-TAT system (TAT-survivin) and transduced it into cells (Supplementary Fig. 2) (15). Herein, we pretreated cardiomyocytes with 1 μM TAT-survivin to determine whether survivin had a protective effect on CRP-induced mitochondrial damage. The CRP-induced reduction in mitochondrial length was attenuated by TAT-survivin pretreatment (Fig. 4A). Furthermore, using MitoSOX Red and CM-H2DCFCA, CRP was found to increase mitochondrial ROS production and accumulation, which was significantly attenuated by TAT-survivin pretreatment (Fig. 4A, B).

Fig. 4.

Fig. 4

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Cardioprotective effect of TAT-survivin in CRP-induced mitochondrial morphologic damage. H9c2 cardiomyocytes were pretreated with or without TAT-survivin (1 μM) and CRP for 24 h. (A) Mitochondrial morphology (green) and mitochondrial superoxide production (red) were co-stained with MitoTracker Green FM and MitoSOX Red. Mitochondrial lengths were quantified using Image J. (B) The time-dependent accumulation of mtROS was measured using CM-H2DCFDA. To determine DRP1 translocation, the following experiments were performed: (C) Protein levels of DRP1 in cytosolic and mitochondrial fractions were quantified using GAPDH and VDAC1, respectively. (D) Confocal immunofluorescence of DRP1 (red) and Tom20 (green) visualized DRP1 location. (E) Immunoblotting of whole-cell lysates showed the expression levels of proteins affected by CRP-induced mitochondrial damage and TAT-survivin pretreatment. Data represent the mean of at least five independent experiments. Scale bar: 5 μm. *P < 0.05, **P < 0.01, ***P < 0.001.

The CRP-induced increase in DRP1 protein levels in the mitochondrial fractions was significantly reduced by TAT-survivin pretreatment (Fig. 4C). Immunofluorescence staining also showed that the red fluorescence signal for DRP1 in mitochondria was increased by CRP but was reduced in TAT-survivin-pretreated cells (Fig. 4D). Additionally, we investigated the effect of TAT-survivin pretreatment on CRP-induced changes in the ERK1/2 and YAP pathway proteins. TAT-survivin pretreatment reduced the CRP-induced YAP expression (Fig. 4E), as well as the expression of their downstream proteins, DRP1, PINK1, and PARK2.

DISCUSSION

In this study, we obtained the following results: 1) CRP increased ROS production in cardiomyocytes and induced mitochondrial damage; 2) the ERK1/2 pathway was involved in CRP-induced mitochondrial fission; 3) the ERK1/2-YAP pathway regulated mitophagy, which removed CRP-damaged mitochondria; and 4) survivin, an anti-apoptotic protein, attenuated CRP-induced mitochondrial damage (Supplementary Fig. 3). To date, few studies have investigated the mechanisms of CRP-induced cardiomyocyte damage in terms of mitochondrial dynamics. Our study explored the signaling pathways involved in CRP-induced mitochondrial damage and showed that survivin may effectively protect cardiomyocytes against inflammatory insult.

CRP is an acute protein that is elevated in the blood during inflammation or tissue damage, making it an important inflammatory marker. Therefore, increased CRP levels are prognostic indicators for patients with atherosclerotic cardiovascular disease. Moreover, there are known mechanisms by which CRP acts as a mediator of atherosclerosis: it induces endothelial dysfunction by decreasing the expression or bioavailability of endothelial nitric oxide synthase or by activating angiotensin II signaling (20, 21). Although the effects of CRP on the myocardium are less studied than those on atherosclerosis, elevated CRP levels are independently associated with severity and poor prognosis in heart failure (2). CRP-overexpressing mice showed a more significant increase in left ventricular end-diastolic filling pressure and systolic dysfunction in response to pressure overload than WT mice, and developed more cardiac fibrosis. Increased IL-6, TGF-beta, and MAC-2-positive macrophage levels were observed in this mechanism (6). Our previous study also demonstrated that CRP induced G0/G1 cell cycle arrest via the ERK1/2-p53 pathway in H9c2 cardiomyocytes (22). However, little is known regarding the altered mitochondrial dynamics in CRP-induced cardiomyocyte damage.

Mitochondrial fission is regulated by the GTPase DRP1, and its post-translational modification controls the elimination of damaged mitochondria and apoptosis in cardiomyocytes, which protects the myocardium from various stimuli or damages it (23). An imbalance in mitochondrial fusion and fission is closely associated with heart failure. Excessive mitochondrial fragmentation due to fission leads to respiratory dysfunction in cardiomyocytes and dilated cardiomyopathy (24). In the present study, CRP-induced mitochondrial fission was accompanied with an increase in DRP1 phosphorylation and mitochondrial expression. CRP did not alter the expression of mitochondrial fusion proteins. These findings suggest that DRP1-dependent fission is a key mechanism underlying CRP-induced changes in mitochondrial dynamics.

We aimed to determine the role of the ERK pathway in CRP-induced mitochondrial fission. Pretreatment with ERK inhibitors decreased CRP-induced mitochondrial fission and DRP-1 phosphorylation, suggesting that the ERK pathway regulates CRP-induced mitochondrial damage. Ras, an upstream member of the ERK1/2 pathway, acts as a sensor of oxidative stress (25), and CRP-induced ROS elevation may have triggered the Ras-ERK1/2 pathway.

In addition, CRP-induced ERK1/2 activation also increased DRP1 expression. We deduced that the downstream targets of ERK1/2 may regulate DRP1 transcription. Recently reports found that YAP, a downstream effector of the Hippo pathway related to cell proliferation regulation, is associated with MAPK, which regulates mitochondrial fission and mitophagy in tumor cells (26, 27). In our study, CRP upregulated the expression of YAP and its cofactor TAZ, and these changes were blocked by ERK inhibitors. In addition, YAP knockdown significantly reduced DRP1 expression and hampered the CRP-induced increase in DRP1 expression. These results suggest that the ERK1/2-YAP pathway regulates the phosphorylation, translocation, and expression of DRP1 during CRP-induced mitochondrial fission.

PINK1 and PARK2 are key mitophagy proteins, which are activated and attached to the mitochondria and recruit ubiquitin to form phagosomes. Doxorubicin accelerates apoptosis in H9c2 cardiomyocytes by upregulating DRP1-mediated fission and PARK2-dependent mitophagy. Parkin is a target gene of Hippo-YAP/TAZ signaling and encodes PARK2. We hypothesized that CRP-induced mitochondrial damage leads to mitophagy and may influence PARK2 expression. In this study, CRP increased the expression of YAP and its downstream target PARK2, whereas YAP knockdown decreased PARK2 protein levels. Furthermore, our finding that YAP knockdown inhibited PINK1 expression was consistent with previous research demonstrating that PINK1-dependent mitophagy is mediated by the Hippo-YAP/TAZ pathway (28). These results evidence that the Hippo-YAP/TAZ pathway is directly involved in CRP-induced mitophagy.

Survivin is a mitochondrial anti-apoptotic protein that has been extensively studied in cancer therapy but not in cardiology. Hagenbuchner et al. demonstrated that survivin overexpression in neuroblastoma regulates DRP1-mediated mitochondrial fission and inhibits cell death (29). Our previous study developed a recombinant TAT-survivin system and found that it recovered doxorubicin-induced cell death in H9c2 cardiomyocytes (15). Additionally, we reported that CRP-induced PTEN upregulation inhibited survivin protein expression via the ERK1/2 pathway (14). Therefore, we hypothesized that transduction of TAT-survivin into H9c2 cells would revert CRP-induced mitochondrial damage. Our experiments showed that mitochondrial fragmentation and mtROS accumulation, increased by CRP, were diminished with TAT-survivin pretreatment. These results evidenced that survivin could prevent CRP-induced mitochondrial damage. However, the amount of phosphorylated ERK1/2 did not appear to be affected by TAT-survivin. Therefore, further studies are needed to determine the stage at which TAT-survivin prevents mitochondrial fission and decreases the expression of mitophagy-related proteins. Generally, mitochondrial fission and coupled mitophagy are involved in cell survival (9). Therefore, the inhibition of mitochondrial fission by TAT-survivin may be owed to a reduction in damaged mitochondria rather than a mechanism that causes cellular damage; this phenomenon warrants further investigation.

Our study revealed that CRP causes mitochondrial damage in cardiomyocytes, which manifests as morphologic changes with increased mitochondrial fission. We also found that the ERK1/2-YAP pathway is involved in CRP-induced changes in mitochondrial dynamics and increased mitophagy, and that TAT-survivin inhibits this pathway. The mechanisms underlying CRP-induced cardiomyocyte damage and the protective effects of TAT-survivin on cardiomyocytes may serve as novel therapeutic targets for cardiomyopathies.

MATERIALS AND METHODS

Reagents and antibodies

Human C-reactive protein (CRP) was obtained from Millipore (Burlington, MA, USA). As sodium azide must be removed from commercial CRP before treatment, we filtered CRP with Tris buffer [10 mM Tris-HCl (pH 7.4), 100 mM NaCl, and 2 mM Ca2+] until the remaining sodium azide was 0.0001%, using Amicon Ultra-0.5 filter (Millipore). Anti-DRP1, anti-MFN1, anti-MFN2, anti-Tom20, anti-ERK1/2, anti-phospho-ERK1/2 (Tyr 204), anti-PARK2, anti-β-actin, and anti-GAPDH antibodies were purchased from Santa Cruz Biotechnology (Dallas, TX, USA). Anti-phospho-DRP1 (Ser616) and anti-OPA1 antibodies were purchased from Cell Signaling Technology (Danvers, MA, USA). Anti-VDAC1/Porin and anti-PINK1 antibodies were purchased from Abcam (Cambridge, UK) and Novus (Centennial, CO, USA), respectively. U0126 (an ERK 1/2 inhibitor) was obtained from Sigma-Aldrich (St. Louis, MO, USA).

Cell culture

H9c2 (2-1) cardiomyocytes (CRL-1446), a rat heart-derived myoblast cell line, were obtained from the American Type Culture Collection. H9c2 cardiomyocytes were routinely cultured in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 100 U/ml penicillin, and 100 μg/ml streptomycin in a humidified atmosphere with 5% CO2 at 37°C. Before all experiments, the cells were adapted to 10% FBS for 24 h and then changed to 0.5% FBS for starvation. After starvation, the cells were treated with 50 μg/ml CRP in 0.5% FBS for 24 h.

Construction and protein purification of TAT-survivin

TAT-survivin fusion protein was manufactured according to a previous study (15). Briefly, TAT-survivin was purified using a Protino Ni-IDA kit (Macherey-Nagel, Düren, Germany). To dialyze imidazole, purified TAT-survivin was loaded onto an Amicon Ultra-15 filter (Millipore) column with PBS. For TAT-survivin transduction, cells were treated 1 μM TAT-survivin for 1 h prior to CRP treatment.

Statistical analysis

Data are presented as means ± standard error. Statistical comparisons were performed with a two-tailed t-test or one-way analysis of variance followed by Tukey’s multiple comparison test, using GraphPad Prism software (Version 8.4.2) (San Diego, CA, USA). A P value < 0.05 was considered statistically significant.

Supplementary methods

A detailed description of the methods is provided in Supplementary methods.

Funding Statement

ACKNOWLEDGEMENTS This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1D1A1B03935941, NRF-2022R1A2C1093325).

Footnotes

bmb-56-12-663-supple.pdf (334.2KB, pdf)

CONFLICTS OF INTEREST

The authors have no conflicting interests.

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Associated Data

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Supplementary Materials

bmb-56-12-663-supple.pdf (334.2KB, pdf)

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