Cardiomyocyte peroxisome proliferator-activated receptor α prevents septic cardiomyopathy via improving mitochondrial function

Xin-xin Zhu1,2,3, Xia Wang1,2,3, Shi-yu Jiao1,2,3, Ye Liu1,2,3, Li Shi1,2,3, Qing Xu4, Jing-jing Wang5, Yun-er Chen1,2,3, Qi Zhang1,2,3, Yan-ting Song6, Ming Wei1,2,3, Bao-qi Yu1,2,3, Jens Fielitz7,8, Frank J. Gonzalez9, Jie Du1,2,3,10, Ai-juan Qu1,2,3
1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University
2 Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education
3 Beijing Key Laboratory of Metabolic Disorder-Related Cardiovascular Diseases, Beijing 100069, China
4 Core Facility Centre, Capital Medical University, Beijing 100069, China
5 Department of Laboratory Animal Capital Medical University, Beijing 100069, China
6 Department of Pathology, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing 100029, China
7 DZHK (German Center for Cardiovascular Research), partner site Greifswald, Mecklenburg-Vorpommern, Germany
8 Department of Internal Medicine B, Cardiology, University Medicine Greifswald, Mecklenburg-Vorpommern, Germany
9 Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
10 Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing 100029, China
Correspondence to: Ai-juan Qu:,
DOI: 10.1038/s41401-023-01107-5
Received: 3 October 2022
Accepted: 8 May 2023
Advance online: 16 June 2023


Clinically, cardiac dysfunction is a key component of sepsis-induced multi-organ failure. Mitochondria are essential for cardiomyocyte homeostasis, as disruption of mitochondrial dynamics enhances mitophagy and apoptosis. However, therapies targeted to improve mitochondrial function in septic patients have not been explored. Transcriptomic data analysis revealed that the peroxisome proliferator-activated receptor (PPAR) signaling pathway in the heart was the most significantly decreased in the cecal ligation puncture-treated mouse heart model, and PPARα was the most notably decreased among the three PPAR family members. Male Pparafl/fl (wild-type), cardiomyocyte-specific Ppara-deficient (PparaΔCM), and myeloid-specific Ppara-deficient (PparaΔMac) mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce endotoxic cardiac dysfunction. PPARα signaling was decreased in LPS-treated wild-type mouse hearts. To determine the cell type in which PPARα signaling was suppressed, the cell type-specific Ppara-null mice were examined. Cardiomyocyte- but not myeloid-specific Ppara deficiency resulted in exacerbated LPS-induced cardiac dysfunction. Ppara disruption in cardiomyocytes augmented mitochondrial dysfunction, as revealed by damaged mitochondria, lowered ATP contents, decreased mitochondrial complex activities, and increased DRP1/MFN1 protein levels. RNA sequencing results further showed that cardiomyocyte Ppara deficiency potentiated the impairment of fatty acid metabolism in LPS-treated heart tissue. Disruption of mitochondrial dynamics resulted in increased mitophagy and mitochondrial-dependent apoptosis in PparaCM mice. Moreover, mitochondrial dysfunction caused an increase of reactive oxygen species, leading to increased IL-6/STAT3/NF-κB signaling. 3-Methyladenine (3-MA, an autophagosome formation inhibitor) alleviated cardiomyocyte Ppara disruption-induced mitochondrial dysfunction and cardiomyopathy. Finally, pre-treatment with the PPARα agonist WY14643 lowered mitochondrial dysfunction-induced cardiomyopathy in hearts from LPS-treated mice. Thus, cardiomyocyte but not myeloid PPARα protects against septic cardiomyopathy by improving fatty acid metabolism and mitochondrial dysfunction, thus highlighting that cardiomyocyte PPARα may be a therapeutic target for the treatment of cardiac disease.

Keywords: sepsis; cardiac dysfunction; mitochondrial dysfunction; mitophagy; inflammation; peroxisome proliferator-activated receptor α

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