Mitochondrial quality control plays a vital role in the maintenance of optimal mitochondrial function. However, its roles and regulation remain ill-defined in cardiac pathophysiology. Here, we tested the hypothesis that PARK2/Parkin, an E3-ligase recently described as being involved in the regulation of cardiac mitophagy, is important for (1) the maintenance of normal cardiac mitochondrial function; and (2) adequate recovery from sepsis, a condition known to induce reversible mitochondrial injury through poorly understood mechanisms. Investigations of mitochondrial and cardiac function were thus performed in wild-type and Park2-deficient mice at baseline and at 2 different times following administration of a sublethal dose of E. coli lipopolysaccharide (LPS). LPS injection induced cardiac and mitochondrial dysfunctions that were followed by complete recovery in wild-type mice. Recovery was associated with morphological and biochemical evidence of mitophagy, suggesting that this process is implicated in cardiac recovery from sepsis. Under baseline conditions, multiple cardiac mitochondrial dysfunctions were observed in Park2-deficient mice. These mild dysfunctions did not result in a visibly distinct cardiac phenotype. Importantly, Park2-deficient mice exhibited impaired recovery of cardiac contractility and constant degradation of mitochondrial metabolic functions. Interestingly, autophagic clearance of damaged mitochondria was still possible in the absence of PARK2 likely through compensatory mechanisms implicating PARK2-independent mitophagy and upregulation of macroautophagy. Together, these results thus provide evidence that in vivo, mitochondrial autophagy is activated during sepsis, and that compensation for a lack of PARK2 is only partial and/or that PARK2 exerts additional protective roles in mitochondria.

Our results show that pretreatment with EP 80317 protected the heart against damage and dysfunction elicited by MI/R, along with a transient reduction in peripheral lipolysis. Our findings support CD36 as a novel target for the treatment of ischaemic cardiopathy.

Insufficient oxygen delivery to organs leads to tissue dysfunction and cell death. Reperfusion, although vital to organ survival, initiates an inflammatory response that may both aggravate local tissue injury and elicit remote organ damage. Polymorphonuclear neutrophil (PMN) trafficking to remote organs following ischaemia/reperfusion (I/R) is associated with the release of lipid mediators, including leucotriene (LT) B4, cysteinyl-LTs (CysLTs) and platelet-activating factor (PAF). Yet, their potentially cooperative role in regulating I/R-mediated inflammation has not been thoroughly assessed. The present study aimed to determine the cooperative role of lipid mediators in regulating PMN migration, tissue oedema and injury using selective receptor antagonists in selected models of I/R and dermal inflammation. Our results show that rabbits, pre-treated orally with BIIL 284 and/or WEB 2086 and MK-0571, were protected from remote tissue injury following I/R or dermal inflammation in an additive or synergistic manner when the animals were pre-treated with two drugs concomitantly. The functional selectivity of the antagonists towards their respective agonists was assessed in vitro, showing that neither BIIL 284 nor WEB 2086 prevented the inflammatory response to IL-8, C5a and zymosan-activated plasma stimulation. However, these agonists elicited LTB4 biosynthesis in isolated rabbit PMNs. Similarly, a cardioprotective effect of PAF and LTB4 receptor antagonists was shown following myocardial I/R in mice. Taken together, these results underscore the intricate involvement of LTB4 and PAF in each other’s responses and provide further evidence that targeting both LTs and PAF receptors provides a much stronger anti-inflammatory effect, regulating PMN migration and oedema formation.

Unacylated ghrelin (UAG), the most abundant form of ghrelin in circulation, has been shown to exert cardioprotective effect in experimental cardiopathies. The present study aimed to investigate the cardioprotective effect of a linear bioactive fragment of UAG against myocardial ischemia-induced injury and dysfunction in C57BL/6 wild type mice and the mechanisms involved. Treatments were administered at doses of 100 (UAG), 1,000 and 3,000 (UAG6−13) nmol/kg at 12 h interval during 14 days prior to 30 min left coronary artery ligation and reperfusion for a period of 6 or 48 h. The infarct area was decreased in a dose-dependent manner at 48 h of reperfusion, with a reduction of 54% at the highest dose of UAG6−13 tested. Myocardial hemodynamics were improved as demonstrated by an increase in cardiac output, maximum first derivative of left ventricular pressure, and preload recruitable stroke work, a load-independent contractility index. Six hours after reperfusion, circulating levels of IL-6 and TNF-α pro-inflammatory cytokines were reduced, and the effect was maintained at 48 h for TNF-α. 5′ AMP-activated protein kinase (AMPK) was activated, while acetyl-CoA carboxylase (ACC) activity was inhibited, along with a decrease in apoptotic protein levels. In isolated hearts, the effect of UAG6−13 was unaffected by the presence of D-Lys3-GHRP-6, a ghrelin receptor (GHSR1a) antagonist, suggesting that the peptide acted through a GHSR1a-independent pathway. The results support the therapeutic application of UAG bioactive peptide fragments against myocardial ischemia/reperfusion injury.

CD36 is a multiligand receptor involved in lipid metabolism. We investigated the mechanisms underlying the cardioprotective effect of CP-3(iv), an azapeptide belonging to a new class of selective CD36 ligands. The role of CP-3(iv) in mediating cardioprotection was investigated because CD36 signaling leads to activation of peroxisome proliferator-activated receptor-g, a transcriptional regulator of adiponectin. CP-3(iv) pretreatment reduced infarct size by 54% and preserved hemodynamics in C57BL/6 mice subjected to 30 min coronary ligation and reperfusion but had no effect in CD36-deficient mice. The effects of CP-3(iv) were associated with an increase in circulating adiponectin levels, epididymal fat adiponectin gene expression, and adiponectin transcriptional regulators (Pparg, Cebpb, Sirt1) after 6 h of reperfusion. Reduced myocardial oxidative stress and apoptosis were observed along with an increase in expression of myocardial adiponectin target proteins, including cyclooxygenase-2, phospho-AMPK, and phospho-Akt. Moreover, CP-3(iv) increased myocardial performance in isolated hearts, whereas blockade of adiponectin with an anti-adiponectin antibody abrogated it. CP-3(iv) exerts cardioprotection against myocardial ischemia and reperfusion (MI/R) injury and dysfunction, at least in part, by increasing circulating and myocardial adiponectin levels. Hence, both paracrine and endocrine effects of adiponectin may contribute to reduced reactive oxygen species generation and apoptosis after MI/R, in a CD36-dependent manner.-Huynh, D. N., Bessi, V. L., Ménard, L., Piquereau, J., Proulx, C., Febbraio, M., Lubell, W. D., Carpentier, A. C., Burelle, Y., Ong, H., Marleau, S. Adiponectin has a pivotal role in the cardioprotective effect of CP-3(iv), a selective CD36 azapeptide ligand, after transient coronary artery occlusion in mice. FASEB J. 32, 807-818 (2018). www.fasebj.orgDespite a substantial decline in mortality rates from cardiovascular diseases and strokes over the past decades, ischemic heart disease (IHD) remains the leading cause of death in developed countries (1) and is expected to burden global health care in the future (2).Altered myocardial metabolism has a central role in the pathogenesis of IHD. Interruption of myocardialenergy supply triggers anaerobic glycolysis to maintain energy requirements, yet the benefits are limited by the formation of byproducts and ionic perturbations, which may lead to contractile dysfunction and cell death (3). Aerobic reperfusion of ischemic hearts, although necessary for myocardial salvage, may further jeopardize function (4). Indeed, reperfusion may lead to myocardial contractile dysfunction, microvascular and endothelial cell injury and cell death (4). Increased production of reactive oxygen species (ROS), intracellular calcium overload, and altered myocardial metabolism are causal