Sepsis is defined as Systemic inflammatory response syndrome (SIRS), which is the most common cause of death in ICU. The main reason for the increased mortality rate of sepsis is septic shock. Septicemia continuously damages the cardiovascular system, and cardiac dysfunction is the main cause of septic shock. Therefore, there is an urgent need for new mechanisms and effective treatment methods to treat cardiac dysfunction caused by sepsis.
Recently, researchers from Capital Medical University published a report on Acta Pharmalogica Sinica magazine entitled “Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function” This study revealed that myocardial cell peroxisome proliferator-activated receptor α (PPARA) prevents infectious cardiomyopathy by improving mitochondrial function.
In clinical practice, cardiac dysfunction is an important component of multiple organ failure caused by sepsis. Mitochondria are essential for the dynamic equilibrium of cardiomyocytes, because the destruction of mitochondrial dynamics enhances mitosis and apoptosis. However, treatment for improving mitochondrial function in sepsis patients has not yet been explored.
Transcription data analysis showed that in the mouse heart model treated with cecal ligation and perforation, the reduction of the PPAR signal pathway in the heart was the most significant, and among the three members of the peroxisome proliferator-activated receptor family, the α reduction is most significant.
Male PPARAfl/fl (wild type), cardiomyocyte-specific PPARA deficiency (PPARAΔCM), and myeloid-specific PPARA defects (PPARAΔMac) mice were intraperitoneally injected with lipopolysaccharide to induce endotoxin-induced cardiac dysfunction.
In the heart of wild-type mice treated with lipopolysaccharide, PPAR α reduced signal transduction. To determine the cell types with PPARα suppressed signals, PPARAnull mice with specific cell types were studied. Myocardial cell rather than myeloid-specific PPARA deficiency leads to the aggravation of endotoxin-induced cardiac dysfunction. The damage of PPARA in myocardial cells aggravates mitochondrial dysfunction, which is manifested as mitochondrial damage, decreased ATP content, decreased mitochondrial complex activity, and increased DRp1/Mfn1 protein level.
RNA sequencing results further showed that the lack of PPARA in cardiomyocytes aggravated the damage of fatty acid metabolism in lipopolysaccharide-treated heart tissues. The disruption of mitochondrial dynamics leads to increased mitochondrial phagocytosis and mitochondrial-dependent cell apoptosis in PPARCM mice. In addition, mitochondrial dysfunction leads to an increase in intracellular reactive oxygen species, leading to IL-6/STAT3/NF- κB signal transduction increases. 3-Methyl Adenine (3-MA, an autophagosome formation inhibitor) can alleviate myocardial mitochondrial dysfunction and cardiomyopathy caused by PPARA interference.
Finally, PPARα pretreatment with agonist WY14643 reduced cardiomyopathy caused by mitochondrial dysfunction in the hearts of lipopolysaccharide-treated mice. Therefore, myocardial cells rather than myeloid PPARα prevent infectious cardiomyopathy by improving fatty acid metabolism and mitochondrial dysfunction, thus emphasizing myocardial cell PPARα may be a target for heart disease treatment.
In summary, this study suggests that in the hearts of sepsis mice, PPARα and the expression of its target genes are inhibited. In cardiac insufficiency caused by sepsis, myocardial cell PPARα instead of myeloid PPARα plays an important role. Myocardial cell-specific PPARA deficiency can aggravate lipopolysaccharide-induced cardiac dysfunction. PPARα in myocardial cells enhanced the damage of mitochondria induced by LPS, and then increased the Phagocytosis of mitochondria.
Cardiomyocyte-specific PPARα defects are activated by IL-6/STAT3/NF- κB signaling pathway, leading to an increase in mitochondrial-dependent cell apoptosis and ROS production induces an inflammatory response. PPARα activation improves cardiac dysfunction in sepsis by improving mitochondrial dysfunction and inflammation. To sum up, myocardial cell PPARα may become a prevention and treatment target for infectious heart dysfunction.
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Reference
Xin-xin Zhu et al. Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function. Acta Pharmacol Sin. 2023 Jun 16. doi: 10.1038/s41401-023-01107-5.