TRPC6 regulates necroptosis in myocardial ischemia/reperfusion injury via Ca2+/CaMKII signaling pathway

Li, Junhao; Zhang, Jiaji; Zhong, Yunlong; Xie, Dongge; Han, Han; Zhang, Zhongqing; Liu, Yong; Li, Shoutian

doi:10.1016/j.cellsig.2024.111344

Cellular Signalling

2024

DOI: 10.1016/j.cellsig.2024.111344

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TRPC6 regulates necroptosis in myocardial ischemia/reperfusion injury via Ca2+/CaMKII signaling pathway

Junhao Li,

Jiaji Zhang,

Yunlong Zhong

et al.

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2024

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Cited by 2 publications

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Cardamonin Attenuates Myocardial Ischemia/Reperfusion-Induced Ferroptosis Through Promoting STAT3 Signaling

Yang,

Wu,

Jiang

et al. 2024

JIR

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Objective Ferroptosis is intricately associated with the pathophysiology processes of myocardial ischemia. Cardamonin (CAR) has been shown to provide significant protection against tissue damage due to multiple ischemia/reperfusion. This study aimed to examine the cardioprotective properties of CAR in myocardial ischemia/reperfusion injury (MIRI) and provide insights into the possible mechanisms involved. Methods An MIRI mice model was conducted by coronary artery ligation, and the effects of CAR on myocardial tissue damage were evaluated by infarct size assessment, echocardiography, and H&E staining. The extent of ferroptosis was detected by examining the levels of ferroptosis-related proteins and lipid reactive oxygen species (ROS). The function pathway of CAR was analyzed by network pharmacology and verified using Western blotting. In addition, we induced hypoxia/reoxygenation (H/R) in cardiomyocytes to detect SLC7A11 expression, ROS level, mitochondrial iron content, and oxidative stress marker levels. The target protein of CAR was identified by Western blotting and molecular docking. We then evaluated the regulatory role of STAT3 on MIRI-induced ferroptosis by silencing STAT3. Results In our study, CAR demonstrated a reduction in myocardial histopathological damage and mitigation of ferroptosis in MIRI mice. Through network pharmacology analysis and Western blotting, our findings indicated that CAR modulates the AGE-RAGE signaling pathway, particularly impacting STAT3. Meanwhile, in vitro experiments revealed that advanced-glycation end products (AGEs) exacerbated H/R-induced ferroptosis, whereas CAR alleviated this ferroptosis in the presence of both AGEs and H/R. CAR was observed to enhance STAT3 expression in H/R+AGRs-treated cardiomyocytes. Molecular docking results demonstrated favorable binding interactions between CAR and STAT3. Our study confirmed that CAR mitigated MIRI-induced myocardial injury and ferroptosis through targeting STAT3 in mice. Conclusion In conclusion, CAR inhibited ferroptosis by activating the STAT3 signaling, thereby mitigating MIRI.

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Cardamonin Attenuates Myocardial Ischemia/Reperfusion-Induced Ferroptosis Through Promoting STAT3 Signaling

Yang,

Wu,

Jiang

et al. 2024

JIR

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Mechanisms and Therapeutic Potential of Multiple Forms of Cell Death in Myocardial Ischemia–Reperfusion Injury

Tsurusaki,

Kizana

2024

IJMS

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Programmed cell death, especially programmed necrosis such as necroptosis, ferroptosis, and pyroptosis, has attracted significant attention recently. Traditionally, necrosis was thought to occur accidentally without signaling pathways, but recent discoveries have revealed that molecular pathways regulate certain forms of necrosis, similar to apoptosis. Accumulating evidence indicates that programmed necrosis is involved in the development of various diseases, including myocardial ischemia–reperfusion injury (MIRI). MIRI occurs when blood flow and oxygen return to an ischemic area, causing excessive production of reactive oxygen species. While this reperfusion is critical for treating myocardial infarction, it inevitably causes cellular damage via oxidative stress. Furthermore, this cellular damage triggers multiple forms of cardiomyocyte death, which is the primary cause of inflammation, cardiac tissue remodeling, and ensuing heart failure. Therefore, understanding the molecular mechanisms of various forms of cell death in MIRI is crucial for therapeutic target discovery. Developing therapeutic strategies to inhibit multiple cell death pathways simultaneously could provide effective protection against MIRI. In this paper, we review the fundamental molecular pathways and MIRI-specific mechanisms of apoptosis, necroptosis, ferroptosis, and pyroptosis. Additionally, we suggest that the simultaneous suppression of multiple cell death pathways could be an effective therapy and identify potential therapeutic targets for implementing this strategy.

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TRPC6 regulates necroptosis in myocardial ischemia/reperfusion injury via Ca2+/CaMKII signaling pathway

Cited by 2 publications

References 48 publications

Cardamonin Attenuates Myocardial Ischemia/Reperfusion-Induced Ferroptosis Through Promoting STAT3 Signaling

Cardamonin Attenuates Myocardial Ischemia/Reperfusion-Induced Ferroptosis Through Promoting STAT3 Signaling

Mechanisms and Therapeutic Potential of Multiple Forms of Cell Death in Myocardial Ischemia–Reperfusion Injury

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