Poly(ADP-ribose) polymerases (PARPs) are central components of the cellular DNA damage response, coordinating DNA repair, chromatin remodeling, and transcriptional regulation. Beyond their established role in oncology, accumulating evidence identifies PARP—particularly PARP-1—as a key modulator of cardiovascular stress responses. In cardiovascular disease states characterized by oxidative and nitrosative stress, PARP activation exerts context-dependent effects: while moderate activation supports genomic integrity and cell survival, excessive or sustained PARP activity leads to depletion of nicotinamide adenine dinucleotide and adenosine triphosphate, mitochondrial dysfunction, inflammatory signaling, and cardiomyocyte death. Preclinical studies consistently demonstrate that genetic or pharmacologic PARP inhibition attenuates ischemia–reperfusion injury, reduces infarct size, limits adverse ventricular remodeling, and preserves myocardial energetics, supporting a cardioprotective role for transient PARP modulation. However, clinical experience with PARP inhibitors, primarily derived from their use in breast cancer susceptibility gene-mutant and homologous recombination–deficient cancers, reveals a more complex cardiovascular safety profile. Pharmacovigilance analyses and real-world data have reported associations with hypertension, thromboembolic events, arrhythmias, and major adverse cardiovascular events, particularly with prolonged systemic exposure and in patients with preexisting cardiovascular comorbidities. This apparent discordance underscores the importance of timing, duration, tissue specificity, and agent-dependent effects in determining cardiovascular outcomes.
Thukral et al. (Tue,) studied this question.