Obesity and metabolic syndrome are major drivers of metabolic heart disease, characterized by profound cardiac energy deficits, structural remodeling, and progression to heart failure. While myocardial mitochondrial dysfunction in obesity is well established, its impact on coronary arteries remains underexplored. This study investigates how high-fat diet (HFD)-induced obesity affects coronary bioenergetics, mitochondrial REDOX balance, and endothelial function. Male Wistar rats were fed a HFD (60
Following myocardial infarction (MI), splenic humoral immune responses contribute to cardiac injury and repair, yet the cardiac signals that govern these responses remain poorly defined. Here, we identified ischemic cardiomyocytes as a source of interleukin 30 (IL-30; the interleukin 27 p28 subunit) and investigated its role in heart–spleen communication. In mice, cardiomyocyte-specific IL-30 deficiency enhanced splenic germinal center responses and signal transducer and activator of transcription 1 (STAT1) phosphorylation. This deficiency increased myocardial IgG deposition, TNF-α expression in Fc gamma receptor III-positive macrophages, and cardiomyocyte apoptosis, while impairing cardiac function and aggravating ventricular remodeling. Recombinant IL-30 suppressed splenic germinal center responses and STAT1 phosphorylation and improved cardiac function. The effects of recombinant IL-30 on germinal center responses and cardiac function were abolished by B cell-specific deletion of glycoprotein 130 (gp130). Furthermore, no detectable improvement in cardiac function was observed following IL-30 treatment in splenectomized mice. In patients with ST-segment elevation myocardial infarction (STEMI; n = 75), lower circulating IL-30 levels were associated with higher peripheral IgG-positive B cell frequencies. In a separate longitudinal cohort of 247 patients with STEMI, low circulating IL-30 was independently associated with adverse left ventricular remodeling at 6 months (odds ratio, 4.44; 95
Myocardial ischemia/reperfusion (I/R) injury has been extensively studied, yet the underlying neuroinflammatory mechanisms are not fully understood. While toll-like receptor 4 (TLR4) is known to be involved in neuropathic pain and neurodegeneration, its role in the central nervous system during myocardial I/R injury, as well as how it modulates neuronal activity to influence cardiac function, remains unclear. In this study, we established a rodent model of myocardial I/R injury by ligating the left anterior descending artery. We found that myocardial I/R injury significantly upregulated TLR4 expression in the spinal dorsal horn, with enhanced TLR4 levels predominantly localized to spinal neurons rather than astrocytes or microglia. Upregulation of TLR4 exhibited functional crosstalk with the calcitonin gene-related peptide (CGRP) receptor, facilitating the transmission of nociceptive signals from the injured myocardium and leading to hyperexcitation of spinal neurons. Both pharmacological inhibition and genetic manipulation of TLR4 signaling resulted in a marked reduction in neuronal activity and attenuated myocardial ischemic injury, accompanied by decreased nociceptive input from the heart to the spinal dorsal horn. Collectively, our findings reveal classic neuroinflammatory signals derived from TLR4 that contribute to neuronal hyperexcitation following myocardial I/R injury. Targeting spinal neuronal TLR4 signaling represents a promising therapeutic strategy for patients with acute myocardial injury.
Adverse cardiac remodeling leads to the development of heart failure following myocardial infarction (MI), yet the immunometabolic signals governing early infarct repair remain poorly understood. Short-chain fatty acids (SCFAs) are important immunometabolic regulators, but their relevance and mechanistic contribution to post-MI repair remain unclear. Here, we integrated clinical observations with genetic and pharmacological intervention studies to investigate the role of the SCFAs-free fatty acid receptor 2 (FFAR2) axis in post-MI repair. Circulating SCFAs levels were markedly decreased in patients with MI, and associated with more complex coronary lesions and a higher risk of major adverse cardiovascular events. In murine MI, SCFAs supplementation reduced infarct expansion, cardiomyocyte death, and cardiac rupture, and improved left-ventricular function. These benefits were lost in global and myeloid-specific Ffar2-deficient mice, demonstrating an essential role for myeloid FFAR2 in SCFA-mediated cardioprotection. Mechanistically, SCFAs activated FFAR2-Gαi signaling in macrophages to suppress RANKL–RANK-driven osteoclast-like macrophage differentiation. thereby enhancing early fibrotic stabilization, reducing cardiomyocyte apoptosis, and improving infarct healing. Pharmacological blockade of osteoclast-like macrophage activation partially rescued impaired healing and cardiac dysfunction in myeloid-specific Ffar2-deficient mice after MI. These findings identify circulating SCFAs as clinically relevant biomarkers associated with coronary lesion complexity and adverse clinical outcomes after MI, and establish the SCFAs–FFAR2 axis as an immune-metabolic pathway that orchestrates macrophage fate and infarct healing. Targeting SCFAs–FFAR2 signaling may represent a therapeutic strategy to limit adverse post-MI remodeling and prevent heart failure.
Obesity induces a systemic low-grade inflammatory activation of the innate immune system potentially impairing early outcomes after myocardial infarction (MI). This study aims to analyse the impact of diet-induced obesity on myelopoiesis, myocardial inflammation, left ventricular function and survival in an experimental mouse model of MI. Male and female C57BL6/J mice were fed either a high-fat (60 kJ
