Mitochondrial protective effects of PARP-inhibition in hypertension-induced myocardial remodeling and in stressed cardiomyocytes

During oxidative stress mitochondria become the main source of endogenous reactive oxygen species (ROS) production. In the present study, we aimed to clarify the effects of pharmacological PARP-1 inhibition on mitochondrial function and quality control processes. L-2286, a quinazoline-derivative PARP inhibitor, protects against cardiovascular remodeling and heart failure by favorable modulation of signaling routes. We examined the effects of PARP-1 inhibition on mitochondrial quality control processes and function in vivo and in vitro. Spontaneously hypertensive rats (SHRs) were treated with L-2286 or placebo. In the in vitro model, 150 μM H2O2 stress was applied on neonatal rat cardiomyocytes (NRCM). PARP-inhibition prevented the development of left ventricular hypertrophy in SHRs. The interfibrillar mitochondrial network were less fragmented, the average mitochondrial size was bigger and showed higher cristae density compared to untreated SHRs. Dynamin related protein 1 (Drp1) translocation and therefore the fission of mitochondria was inhibited by L-2286 treatment. Moreover, L-2286 treatment increased the amount of fusion proteins (Opa1, Mfn2), thus preserving structural stability. PARP-inhibition also preserved the mitochondrial genome integrity. In addition, the mitochondrial biogenesis was also enhanced due to L-2286 treatment, leading to an overall increase in the ATP production and improvement in survival of stressed cells. Our results suggest that the modulation of mitochondrial dynamics and biogenesis can be a promising therapeutical target in hypertension-induced myocardial remodeling and heart failure. [Display omitted] •PARP-inhibition prevented mitochondrial fragmentation inhibiting Drp1 translocation and increasing the fusion proteins•PARP-inhibition preserved mitochondrial structure and mitochondrial genome integrity•L-2286 increased the amount of mitochondria activating the mitochondrial biogenesis•L-2286 preserved mitochondrial structure and function in stress situations•Mitochondrial protection of PARP-inhibitors can account for their cardioprotective effect