Late-life enalapril administration affects mitochondrial biogenesis in the heart of old rats

Inhibition of the renin-angiotensin system has been shown to ameliorate age-related mitochondrial alterations in several rat tissues and to increase rodent lifespan. Here, we investigated the effect of late-life enalapril administration on mitochondria biogenesis, antioxidant enzymes content and mtDNA levels in rat hearts and sought to discern the effects of enalapril mediated by nitric oxide (NO) from those independent from NO signaling. Fischer 344×Brown Norway rats were randomly assigned to receive enalapril (n=4), the NO synthase (NOS) inhibitor NG-nitro-L-arginine methylester (L-NAME; n=4), enalapril + L-NAME (n=4), or placebo (n=4) from 24 to 27 months of age. Enalapril in combination or not with L-NAME induced a marked increase in mitochondrial DNA content. Accordingly, a higher content of mitochondrial biogenesis proteins [i.e., peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and mitochondrial transcription factor A (TFAM)] and mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) protein have been observed in the same two groups. Our data indicate that enalapril enhances mitochondrial biogenesis in the heart of aged rats as a result of a concerted modulation of NO and angiotensin II signaling. As both mtDNA content and mitochondrial biogenesis are crucial for preserving cellular respiratory capacity, and PGC-1α is protective against ROS production and oxidative damage, our results support the hypothesis that the beneficial effect of enalapril on the heart is mediated at least partly by mitigation of oxidative stress.