Cardiovascular Research最新文献

Aims: Myocardial ischemia‒reperfusion (I/R) injury triggers a robust inflammatory storm cascade that critically compromises reperfusion efficacy following acute myocardial infarction (AMI). Enhanced efferocytosis by cardiac resident macrophages (RMs) has therapeutic potential for inflammation resolution. The unsaturated long‒chain fatty acid Maresin1 (MaR1) exhibits potent anti‒inflammatory properties that is devoid of immunosuppressive effects. However, its therapeutic potential in myocardial I/R injury and regulatory mechanisms in cardiac RMs remains unexplored.

Methods and results: A clinical case‒control study was conducted and revealed a negative association between circulating MaR1 levels and inflammatory markers and the severity of I/R injury in patients with ST‒elevation myocardial infarction (STEMI). Mice treated with MaR1 after myocardial I/R injury showed improvements in cardiac function and efferocytosis by cardiac RMs. Genetic ablation of cardiac RMs abolished MaR1‒mediated cardioprotection. To explore the mechanism underlying this protection, we performed transcriptomic, metabolomic and lipidomic analyses and identified fatty acid β‒oxidation potentiation as a key metabolic signature in MaR1‒treated RMs. Morever, MaR1 directly bound peroxisome proliferator‒activated receptor γ (PPARγ), inducing the transcriptional activation of its downstream efferocytosis‒related target CD204. Specific knockout of PPARγ in RMs significantly attenuated MaR1‒enhanced efferocytosis. Notably, oral supplementation with the MaR1 precursor docosahexaenoic acid (DHA) recapitulated these cardioprotective effects.

Conclusions: Our findings prove that MaR1 plays a protective role in myocardial I/R injury by facilitating efferocytosis by RMs and the resolution of inflammation. These results offer novel therapeutic perspectives for the management of myocardial I/R injury.

Aims: We and others discovered a highly conserved mitochondrial transmembrane microprotein, named Mitoregulin (Mtln), that supports lipid metabolism. We reported that Mtln strongly binds cardiolipin (CL), increases mitochondrial respiration and Ca2+ retention capacities, and reduces reactive oxygen species (ROS). Here we extend our observation of Mtln-CL binding and examine Mtln influence on cristae structure and mitochondrial membrane integrity during stress.

Methods and results: We demonstrate that mitochondria from constitutive- and inducible Mtln-knockout (KO) mice are susceptible to membrane freeze-damage and that this can be rescued by acute Mtln re-expression. In mitochondrial-simulated lipid monolayers, we show that synthetic Mtln decreases lipid packing and monolayer elasticity. Lipidomics revealed that Mtln-KO heart tissues show broad decreases in 22:6-containing lipids and increased cardiolipin damage/remodeling. Lastly, we demonstrate that Mtln-KO mice suffer worse myocardial ischemia-reperfusion injury, hinting at a translationally relevant role for Mtln in cardioprotection.

Conclusion: Our work supports a model in which Mtln binds cardiolipin and stabilizes mitochondrial membranes to broadly influence diverse mitochondrial functions, including lipid metabolism, while also protecting against stress.

Aims: Mitochondria serve as central hubs for aerobic metabolism and regulators of cell fate. Damage to mitochondria induced by oxidative stress contributes to cardiac injury. We investigate whether oxidative stress causes the release of mitochondrial into the extracellular space and whether these extracellular mitochondria (EM) mediate the detrimental effect of oxidative stress.

Methods and results: AC16 cardiomyocytes were exposed to sublethal doses of H2O2 to collect mitochondria released into the conditioned culture medium. These EM were compared with intracellular mitochondria (IM) for morphology, size, membrane potential, and metabolic profile using LC-MS/MS based metabolomics. Cellular ceramide content was measured by lipidomics to determine the role of ceremide synthesis in mitochondrial release. EM were tested for the ability to activate THP-1 macrophages.Oxidants caused an increase of EM. While EM from stressed cells did not show significant difference from those of non-stressed cells in overall morphology, size or surface charge, EM exhibited disrupted cristae structure, smaller size, reduced membrane potential, and decreased levels of NAD, ATP, ADP and AMP compared to IM. H2O2 treatment upregulated several ceramide species in AC16 cells and inhibition of ceramide synthesis markedly reduced EM released under oxidative stress. Functionally, EM activated M1 and M2 like macrophages, as indicated by increased expression of the cytokine markers TNFα and CD163.

Conclusions: Oxidative stress enhanced the release of mitochondria from cardiomyocytes into the extracellular space. These EM differ from IM in their smaller sizes, reduced membrane potential, and depressed metabolic state. At high abundance, EM act as mediators that promote macrophage activation.