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
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
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
The mitochondrial permeability transition pore (mPTP) opening is a phenomenon in which the inner mitochondrial membrane abruptly becomes permeable when matrix calcium reaches a critical threshold. Despite 5 decades of intensive research, no protein has been universally accepted as essential for mPTP opening, limiting mechanistic understanding and raising questions about the validity of mPTP-targeted strategies to mitigate cardiac ischemia–reperfusion (I/R) injury. Here, we discuss convergent findings from two independent laboratories identifying the innate immune receptor NLRX1 as an unexpected, essential requirement for mPTP activity. NLRX1 is the only NOD-like receptor (NLR) that is targeted to the mitochondrion. NLRX1 deficiency abolishes (1) calcium-induced mPTP opening, (2) cyclosporine A sensitivity of the pore, and (3) mitochondrial calcium release following cardiac I/R. To test whether loss of mPTP function aligns with loss of NLRX1 across evolution, we performed forward and reciprocal bioinformatic (Blastp) searches and found that species reported to lack an mPTP (e.g., Artemia franciscana and Drosophila melanogaster) also lack NLRX1, further supporting a mandatory role for NLRX1 in mPTP occurrence. Notably, NLRX1-deficient hearts can exhibit increased, rather than decreased, I/R injury at specific ischemia durations. This mirrors reports that deletion of established mPTP regulators (e.g., Ppif) may also worsen injury under defined conditions, consistent with context-dependent, potentially protective roles for transient mPTP activity (e.g., mitochondrial calcium release, PI3K/Akt signaling). In summary, we propose that NLRX1 is the only currently identified protein that is strictly required for mPTP opening, and that indiscriminate inhibition of the mPTP is unlikely to represent a universally effective cardioprotective strategy against I/R injury.
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 (
