Key result
PARP-1 inhibition with L-2286 prevented left ventricular hypertrophy in spontaneously hypertensive rats and improved mitochondrial dynamics, biogenesis, and survival in stressed cardiomyocytes.
Why the study?
During oxidative stress mitochondria become the main source of endogenous ROS production, and the effects of pharmacological PARP-1 inhibition on mitochondrial function and quality control processes remained to be clarified.
Does PARP-1 inhibition with L-2286 prevent left ventricular hypertrophy and improve mitochondrial function in spontaneously hypertensive rats and stressed cardiomyocytes?
Does PARP-1 inhibition with L-2286 prevent left ventricular hypertrophy and improve mitochondrial function in spontaneously hypertensive rats and stressed cardiomyocytes?
PARP-1 inhibition with L-2286 prevents hypertension-induced left ventricular hypertrophy and preserves mitochondrial dynamics and biogenesis in preclinical models.
Hypothesis-generating for PARP-1 inhibition in hypertensive LVH; human trials needed before clinical translation.
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.
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Horváth et al. (2021) studied Hypertension-induced myocardial remodeling. L-2286 (PARP inhibitor) vs. Placebo / Untreated was evaluated on Left ventricular hypertrophy and mitochondrial quality control processes. PARP-1 inhibition with L-2286 prevented left ventricular hypertrophy in spontaneously hypertensive rats and improved mitochondrial dynamics, biogenesis, and survival in stressed cardiomyocytes.
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