Grant Abstract: Lipid Deposition in the Right Ventricle in Pulmonary Arterial Hypertension

Grant Number: 5R01HL122417-04
PI Name: Hemnes
Project Title: Lipid Deposition in the Right Ventricle in Pulmonary Arterial Hypertension

Abstract: We hypothesize that L-carnitine supplementation will prevent and reverse myocardial lipotoxicity in the PAH RV by increasing fatty acid oxidation. As a prelude to a phase II human trial, we will test this hypothesis using a murine model of PAH with a mutation in bone morphogenetic protein receptor type II (BMPR2). This model recapitulates exactly the FA metabolic defects we observed in humans making it ideal to ultimately translate our findings back to humans. We will examine the effect of carnitine supplementation on in vivo myocardial lipid content and RV function using proton magnetic resonance spectroscopy at 15Tesla field strength. We will assess ex vivo oxidation of fatty acid substrates in the RV using high-resolution respirometry. Metabolomic profiling will allow us to identify additional pathways that are altered with carnitine supplementation.
Aim 1: To test the hypothesis that carnitine supplementation will prevent and reverse myocardial lipotoxicity in the PAH RV. We will supplement BMPR2 mice with carnitine or placebo for 10 weeks. Studies will be performed at the time of BMPR2 transgene activation (prevention) and after PAH is established (treatment). The amount and composition of RV lipid will be examined in vivo using a 15T small animal MRI scanner as well as Oil red O staining. We will assess lipotoxicity by measuring ceramides (mass spectrometry) and apoptosis (Annexin V, TUNEL). Changes in RV function (ejection fraction, contractility) and pulmonary hemodynamics will be measured using cardiac MRI and pressure volume loops.
Aim 2: To examine the effect of carnitine supplementation on fatty acid oxidation in the PAH RV. Using the same animals tested in Aim 1, we will examine the effect of carnitine on RV oxygen consumption and metabolism of fatty acid substrates using high-resolution respirometry. These detailed studies of mitochondrial function will determine the mechanism of impaired FA oxidation in the PAH RV and whether carnitine rescues the defect. Mitochondrial oxidant stress will be measured by RV isoprostanes. Metabolic profiling of RV tissue will directly quantify changes in fatty acid and carnitine species and identify additional pathways altered by carnitine supplementation.


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