Abstract 18962: MrpL48 is Associated with Impaired Mitochondrial Function and Blood Pressure Regulation in Genetic Hypertension

Abstract

BACKGROUND: Aerobic metabolism has been implicated in the pathogenesis of cardiovascular diseases but the underlying genes that contribute to this process are incompletely understood. Here, we identified a novel gene within a previously mapped blood pressure QTL on rat chromosome 1 and demonstrate that the nuclear encoded mitochondrial ribosomal protein 48 (MrpL48) contributes to impaired aerobic metabolism and elevated blood pressure phenotypes in rats and mice. METHODES: We measured telemetric blood pressure and generated genome wide expression signatures in kidneys of 30 rat recombinant inbred strains that were established from the spontaneously hypertensive rat (SHR) and the BN normotensive reference strain as well as from chromosome 1 congenic rats spanning the chromosome 1 blood pressure QTL. This led to a positional candidate gene which was subsequently analyzed at the molecular level. We investigated mitochondrial bioenergetic processes and translation in vitro and ex vivo and subsequently monitored blood pressure in MrpL48 knockout mice by telemetry. RESULTS: Expression analysis in the congenic line as well as the HXB/BXH recombinant inbred panel showed that variation at the MrpL48 locus resulted in altered gene expression and significantly correlated with blood pressure levels. We demonstrated that MrpL48 plays an important role in mitochondrial translation and subsequently mitochondrial function in vitro and in vivo. MrpL48 knockout mice showed significantly increased pulse pressure levels. CONCLUSION: Our findings suggest that MrpL48 plays an important role in mitochondrial dysfunction and blood pressure regulation and identifies a so far unappreciated mechanism of blood pressure regulation.