Exercise Reveals Proline Dehydrogenase as a Potential Target in Heart Failure

The benefits of physical activity in cardiovascular diseases have long been appreciated. However, the molecular mechanisms that trigger and sustain the cardiac benefits of exercise are poorly understood, and it is anticipated that unveiling these mechanismswill identify novel therapeutic targets. In search of these mechanismswe took advantage of unbiasedRNA-sequencing(RNA-seq) technology to discover cardiac gene targetswhose expression is disrupted in heart failure (HF) and rescued by exercise in a ratmodel. Upon exhaustive validation in a separate rat cohort (qPCR) and human datasets, we shortlisted 16 targets for a cell-based screening, aiming to evaluate whether targeted disruption of these genes with silencing RNAwould affect the abundance of a CVD biomarker (BNP, B-type natriuretic peptide) in human cardiomyocytes. Overall, these experiments showed that Proline De- hydrogenase (PRODH) expression is reduced in human failing hearts, rescued by exercise in a rat model of HF, and its targeted knockdownincreases BNPexpression in human cardiomyocytes. Onthe other hand, overexpres- sion of PRODHincreases the abundance ofmetabolism-related gene transcripts, and PRODHappears to be crucial to sustain normal mitochondrial function and maintenance of ATP levels in human cardiomyocytes in a hypoxic environment, aswell as for redox homeostasis in both normoxic and hypoxic conditions. Altogether our findings showthat PRODH is a novel molecular target of exercise in failing hearts and highlight its role in cardiomyocyte physiology, thereby proposing PRODH as a potential experimental target for gene therapy in HF.