PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy.

Autor:	Chen X; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K., Ruiz-Velasco A; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K., Zou Z; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K., Hille SS; Department of Internal Medicine III, University of Kiel, Kiel, Germany.; DZHK, Partner Site Hamburg/Kiel/Lübeck, German Centre for Cardiovascular Research, Kiel, Germany., Ross C; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K., Fonseka O; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K., Gare SR; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K., Alatawi NHO; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K., Raja R; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K., Zhang J; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K., Kaur N; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K., Zhao X; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K., Morrell-Davies H; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K., Miller JM; Surgery Department, Baylor College of Medicine, Houston, TX., Abouleisa RRE; Surgery Department, Baylor College of Medicine, Houston, TX., Ou Q; Institute of Molecular Cardiology, University of Louisville, Louisville, KY., Frank D; Department of Internal Medicine III, University of Kiel, Kiel, Germany.; DZHK, Partner Site Hamburg/Kiel/Lübeck, German Centre for Cardiovascular Research, Kiel, Germany., Rutter MK; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K.; Diabetes, Endocrinology and Metabolism Centre, National Institute for Health and Care Research Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester University Hospitals National Health Service Foundation Trust, Manchester, U.K., Pinali C; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K., Wang T; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K., Mohamed TMA; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K.; Surgery Department, Baylor College of Medicine, Houston, TX.; Institute of Molecular Cardiology, University of Louisville, Louisville, KY., Müller OJ; Department of Internal Medicine III, University of Kiel, Kiel, Germany.; DZHK, Partner Site Hamburg/Kiel/Lübeck, German Centre for Cardiovascular Research, Kiel, Germany., Liu W; Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, U.K.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2024 Nov 01; Vol. 73 (11), pp. 1805-1820.
DOI:	10.2337/db24-0240
Abstrakt:	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. (© 2024 by the American Diabetes Association.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu