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 transverse aortic constriction (TAC) in both cardiac-specific PRODH knockout and overexpression mice. Our results indicate that PRODH expression is suppressed post-TAC. Cardiac-specific PRODH knockout mice exhibited worsened cardiac dysfunction, while mice with PRODH overexpression demonstrated a protective effect. Additionally, 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 (TCA) cycle intermediates, enhance energy production, and restore glutathione redox balance. In summary, our findings suggest PRODH as a modulator of cardiac bioenergetics and redox homeostasis duing cardiac remodeling induced by pressure overload. This highlights the potential of PRODH as a therapeutic target for cardiac remodeling. Overall design: To investigate the role of PRODH in the regulation of pressure overload-induced cardiac remodeling, cardiac-specific overexpression of PRODH was achieved through AAV9-mediated delivery system. Two types of viruses, AAV9-Vector and AAV9-PRODH, were injected into mice, and transverse aortic constriction (TAC) surgery was performed. Four weeks post-surgery, cardiac tissues were collected for RNA-seq analysis. The primary aim of our study was to compare the changes between the TAC group and the Sham group in AAV9-Vector mice, as well as to assess the transcriptomic differences between the AAV9-Vector and AAV9-PRODH groups in mice following TAC surgery.