PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy

Obesity-induced lipid overload in cardiomyocytes contributes to profound oxidative stress and cardiomyopathy, culminating in heart failure. In this study, we investigate a novel mechanism whereby lipids accumulate in cardiomyocytes, and seek the relevant treatment strategies. P21-activated kinase 3 (PAK3) was elevated in obese human myocardium, and the murine hearts and cardiomyocytes upon diet- or fatty acid–induced stress, respectively. Mice with cardiac-specific overexpression of PAK3 were more susceptible to the development of cardiac dysfunction upon diet stress, at least partially, because of increased deposition of toxic lipids within the myocardium. Mechanistically, PAK3 promoted the nuclear expression of sterol regulatory element binding protein 1c (SREBP1c) through activation of mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase β-1 (S6K1) pathway in cardiomyocytes, resulting in abnormal lipid genes profile, accumulation of excessive lipids, and oxidative stress. More importantly, PAK3 knockdown attenuated fatty acid–induced lipotoxicity and cell death in rat and human cardiomyocytes. More importantly, the S6K1 or SREBP1c inhibitor alleviated PAK3-triggered intracellular lipid overload and cardiac dysfunction under obese stress. Collectively, we have demonstrated that PAK3 impairs myocardial lipid homeostasis, while inhibition of cardiac lipotoxicity mitigates cardiac dysfunction. Our study provides a promising therapeutic strategy for ameliorating obesity cardiomyopathy. Article Highlights

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Journal
Diabetes
Published
2024-08-13
DOI
https://doi.org/10.2337/db24-0240
Citations
10
Primary Topic
Cardiac electrophysiology and arrhythmias
Type
article
Field-Weighted Citation Impact
4.02

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article

PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy

Susanne S. Hille, Andrea Ruiz‐Velasco, Jessica M. Miller, Rida Raja et al.
10 citations
Diabetes
Cardiac electrophysiology and arrhythmias
4.02
article

PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy

Susanne S. Hille, Andrea Ruiz‐Velasco, Jessica M. Miller, Rida Raja, Zhiyong Zou, Christian Pinali, Tamer Mohamed, Sanskruti Ravindra Gare, Martin K. Rutter, Nasser hawimel o Alatawi, Derk Frank, Namrita Kaur, Jiayan Zhang, Oveena Fonseka, Oliver Josef Müller, Qinghui Ou, Xiangjun Zhao, Riham R. E. Abouleisa, Wei Liu, Tao Wang, Xinyi Chen, Henrietta Morrell-Davies, Claire Ross
article en
10 citations

Abstract

Obesity-induced lipid overload in cardiomyocytes contributes to profound oxidative stress and cardiomyopathy, culminating in heart failure. In this study, we investigate a novel mechanism whereby lipids accumulate in cardiomyocytes, and seek the relevant treatment strategies. P21-activated kinase 3 (PAK3) was elevated in obese human myocardium, and the murine hearts and cardiomyocytes upon diet- or fatty acid–induced stress, respectively. Mice with cardiac-specific overexpression of PAK3 were more susceptible to the development of cardiac dysfunction upon diet stress, at least partially, because of increased deposition of toxic lipids within the myocardium. Mechanistically, PAK3 promoted the nuclear expression of sterol regulatory element binding protein 1c (SREBP1c) through activation of mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase β-1 (S6K1) pathway in cardiomyocytes, resulting in abnormal lipid genes profile, accumulation of excessive lipids, and oxidative stress. More importantly, PAK3 knockdown attenuated fatty acid–induced lipotoxicity and cell death in rat and human cardiomyocytes. More importantly, the S6K1 or SREBP1c inhibitor alleviated PAK3-triggered intracellular lipid overload and cardiac dysfunction under obese stress. Collectively, we have demonstrated that PAK3 impairs myocardial lipid homeostasis, while inhibition of cardiac lipotoxicity mitigates cardiac dysfunction. Our study provides a promising therapeutic strategy for ameliorating obesity cardiomyopathy. Article Highlights

DiabetesVol. 73(11)
University of Louisville (US), Baylor College of Medicine (US), Manchester Academic Health Science Centre (GB), University of Manchester (GB), Hochschule für Angewandte Wissenschaften Kiel (DE), Christian-Albrechts-Universität zu Kiel (DE), University Hospital Schleswig-Holstein (DE), German Centre for Cardiovascular Research (DE), NIHR Manchester Biomedical Research Centre (GB), Clinical Research Center Kiel (DE), University of Lübeck (DE)
U.S. Department of Defense, American Heart Association, National Institute for Health and Care Research, British Heart Foundation, University of Manchester, National Institutes of Health, Manchester Biomedical Research Centre
Good health and well-being
Openalex Percentile: Top 5%
Cardiac electrophysiology and arrhythmias
4.02
DOIOpen Access PDFOpenAlex
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