Authors: Chaitanya A Kulkarni, Alexander S Milliken, Paul S Brookes
Published: 2019-10-16
DOI: 10.1161/res.125.suppl_1.302
Source: Full article
Metabolic acidosis is the hallmark of the ischemic period of ischemia-reperfusion injury and acidic pH is cardioprotective via unclear mechanisms. We previously reported induction of neomorphic activities in several dehydrogenase enzymes under acidic pH, leading to accumulation of non-canonical metabolite L-2-hydroxyglutarate (2-HG). Lysine deacetylase SIRT1 is required for cardioprotection via ischemic preconditioning (IPC) and 2-HG levels are elevated in IPC in a SIRT1 dependent manner. We hypothesized that acidic pH may be an independent variable that partly drives the metabolic character of not only ischemia, but also IPC. This hypothesis was tested using LC-MS/MS based metabolomics analysis of perfused hearts. Exposure of hearts to ischemia, hypoxia, IPC or intracellular acidosis resulted in partially overlapping metabolomes, with a number of metabolic adaptations previously attributed as either ischemic or IPC-driven, being induced by acidic pH alone. Furthermore, we observed that SIRT1 activator β-nicotinamide adenine mononucleotide induced cellular acidification in isolated cardiomyocytes. In the same cells it was observed that SIRT1 activation resulted in inhibition of sodium proton exchanger NHE1. These results suggest (i) a novel signaling mechanism in which SIRT1 is a cellular pH regulator via NHE1, and (ii) a role for acidic pH as a link between SIRT1 and cardioprotective metabolic adaptations.