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
Cardioprotection induced by repetitive ischemia/reperfusion (I/R) is not confined to the ischemic region but may extend to distant myocardial territories, a phenomenon termed intracardiac remote ischemic preconditioning (icRIPC). The present study aimed to evaluate the delayed effects of icRIPC on infarct size (IS), left ventricular (LV) function (LVF), and myocardial gene and protein expression. icRIPC was induced in 13 pigs by 3 cycles of 10 min ischemia/10 min reperfusion of the left anterior descending coronary artery (LAD) (conditioning) territory, followed 24 h later by reperfused acute myocardial infarction (AMI) of the left circumflex artery (LCx) (infarcted) territory, induced by 90-min percutaneous balloon occlusion of the mid LCx followed by reperfusion (group icRIPC-AMI). Thirteen additional pigs underwent a sham icRIPC procedure followed by reperfused LCx AMI 24 h later and served as controls (group AMI). Five pigs from each group were euthanized at 3 days, and myocardial expression of nine selected genes was quantified by RT-qPCR in the distal LAD and LCx territories. Protein expression of the two significantly upregulated genes was assessed by Western blot. The remaining eight pigs in each group were followed for 1 month. At 3 days after reperfused AMI, superoxide dismutase-2 (SOD2) protein expression was increased in the infarcted LCx territory of the icRIPC-AMI group, whereas inducible nitric oxide synthase (iNOS/NOS2) protein expression was increased in the distal LAD territory. At 1 month, IS was lower in the icRIPC-AMI than in the AMI group (8.4±3.7
Malonate, an inhibitor of mitochondrial succinate dehydrogenase (SDH), protects against ischemia–reperfusion injury (IRI) when given at early reperfusion, making it a promising therapeutic agent for acute myocardial infarct (AMI) and stroke patients. Prior to clinical studies, it is essential to identify potential translational roadblocks. One such barrier is the metabolic signature of the heart. Here, we explored whether and how the metabolic signature of the heart drive cardiac IRI and modulate malonate protection. Langendorff-perfused mouse hearts were subjected to 30 min ischemia (I) followed by 90 min reperfusion (R), with or without 5mM disodium malonate administered during the first 5 min reperfusion. Cardiac IRI and malonate protection were examined under four metabolic conditions increasing in metabolic complexity: glucose-only (G), glucose + glutamine (GG), GG + fatty acid (F), F + insulin (Ins). Metabolomic profiling and survival kinases were evaluated at end-ischemia and at 7 min of reperfusion ± malonate. Additional experiments examined the effects of glucose, lactate, and low pH on malonate efficacy. IRI (
During heart failure (HF), gene and protein expression profiles undergo extensive compensatory and pathological remodeling. We previously observed that fast skeletal myosin binding protein-C (fMyBP-C) is upregulated in diseased mouse hearts. While fMyBP-C shares significant homology with its cardiac paralog, cardiac myosin binding protein-C (cMyBP-C), there are key differences that may affect cardiac function. However, the consequence of cardiac expression of fMyBP-C is unknown. Here, we aim to elucidate the impact of fMyBP-C expression on cardiac function and pathology. To determine the sufficiency of fMyBP-C to cause cardiac dysfunction, we generated cardiac-specific fMyBP-C over-expression mice. These mice were crossed into cMyBP-C null mice to assess the effect of fMyBP-C in the complete absence of cMyBP-C. Finally, fMyBP-C null mice underwent transverse aortic constriction (TAC) to define the requirement of fMyBP-C in HF. We confirmed the upregulation of fMyBP-C in several models of cardiac disease, including lineage tracing models. Low levels of fMyBP-C caused mild cardiac remodeling and sarcomere dysfunction. Exclusive expression of fMyBP-C in a HF model exacerbated cardiac pathology. Furthermore, reduction of fMyBP-C expression by shRNA in HF improved cardiac function. Following pressure overload, fMyBP-C null mice demonstrated greater resistance to cardiac decompensation. Mechanistically, our data suggest the differential regulation of the myosin super-relaxed state by cMyBP-C and fMyBP-C plays a contributing role. These findings suggest the elevated expression of fMyBP-C in diseased hearts is a pathological response. Targeted therapies to prevent upregulation of fMyBP-C may prove beneficial in the treatment of HF.
