Mesaconate significantly attenuated cardiac injury, improved systolic function, and reduced infarct size in myocardial ischemia/reperfusion injury in mice.
Does mesaconate reduce myocardial ischemia/reperfusion injury and cardiovascular aging in murine models?
Mesaconate is a promising metabolically compatible therapeutic candidate that protects against myocardial ischemia/reperfusion injury and aging-related cardiovascular pathology by activating GPR35 to suppress macrophage ferroptosis and inflammation.
This study aimed to investigate the cardioprotective role and underlying mechanisms of the endogenous metabolite mesaconate in both acute and chronic cardiovascular disease models, with a focus on its regulation of macrophage inflammation. Transcriptomic profiling and functional validation in bone marrow-derived macrophages suggested GPR35 as a potential target of mesaconate. Further mechanistic studies revealed that mesaconate alleviates macrophage ferroptosis via GPR35, thereby contributing to its anti-inflammatory effects. In a myocardial ischemia/reperfusion model, mesaconate significantly attenuated cardiac injury, improved systolic function, and reduced infarct size, while myeloid-specific GPR35 knockdown abolished these protective effects. In aged mice, mesaconate ameliorated cardiac hypertrophy and vascular dysfunction, effects closely associated with suppressed macrophage inflammation. Collectively, this study demonstrates for the first time that mesaconate alleviates macrophage inflammation by activating GPR35 to suppress ferroptosis, confers GPR35-dependent cardioprotection in ischemic injury, and mitigates aging-related cardiovascular pathology, highlighting mesaconate as a promising therapeutic candidate for inflammatory cardiovascular diseases.
Zhu et al. (Wed,) conducted a other in myocardial ischemia/reperfusion injury and cardiovascular aging in mouse models. mesaconate vs. sham operation or control group without mesaconate was evaluated on cardiac injury, systolic function (left ventricular ejection fraction and fractional shortening), and infarct size in myocardial ischemia/reperfusion model. Mesaconate significantly attenuated cardiac injury, improved systolic function, and reduced infarct size in myocardial ischemia/reperfusion injury in mice.