Proline metabolic reprogramming modulates cardiac remodeling induced by pressure overload in the heart

Metabolic reprogramming is critical in the onset of pressure overload-induced cardiac remodeling. Our study reveals that proline dehydrogenase (PRODH), the key enzyme in proline metabolism, reprograms cardiomyocyte metabolism to protect against cardiac remodeling. We induced cardiac remodeling using...

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Published inScience advances Vol. 10; no. 19; p. eadl3549
Main Authors Lv, Qingbo, Li, Duanbin, Zhao, Liding, Yu, Pengcheng, Tao, Yecheng, Zhu, Qiongjun, Wang, Yao, Wang, Meihui, Fu, Guosheng, Shang, Min, Zhang, Wenbin
Format Journal Article
LanguageEnglish
Published United States American Association for the Advancement of Science 10.05.2024
Subjects
Animals
Biomedicine and Life Sciences
Cardiomegaly - etiology
Cardiomegaly - metabolism
Cardiomegaly - pathology
Disease Models, Animal
Diseases and Disorders
Energy Metabolism
Life Sciences
Male
Metabolic Reprogramming
Mice
Mice, Knockout
Myocardium - metabolism
Myocardium - pathology
Myocytes, Cardiac - metabolism
Oxidation-Reduction
Proline - metabolism
Proline Oxidase - genetics
Proline Oxidase - metabolism
Rats
SciAdv r-articles
Ventricular Remodeling
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Summary:Metabolic reprogramming is critical in the onset of pressure overload-induced cardiac remodeling. Our study reveals that proline dehydrogenase (PRODH), the key enzyme in proline metabolism, reprograms cardiomyocyte metabolism to protect against cardiac remodeling. We induced cardiac remodeling using transverse aortic constriction (TAC) in both cardiac-specific PRODH knockout and overexpression mice. Our results indicate that PRODH expression is suppressed after TAC. Cardiac-specific PRODH knockout mice exhibited worsened cardiac dysfunction, while mice with PRODH overexpression demonstrated a protective effect. In addition, we simulated cardiomyocyte hypertrophy in vitro using neonatal rat ventricular myocytes treated with phenylephrine. Through RNA sequencing, metabolomics, and metabolic flux analysis, we elucidated that PRODH overexpression in cardiomyocytes redirects proline catabolism to replenish tricarboxylic acid cycle intermediates, enhance energy production, and restore glutathione redox balance. Our findings suggest PRODH as a modulator of cardiac bioenergetics and redox homeostasis during cardiac remodeling induced by pressure overload. This highlights the potential of PRODH as a therapeutic target for cardiac remodeling.
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These authors contributed equally to this work.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adl3549