Disrupting Nicotinamide Nucleotide Transhydrogenase Prevents Cardiometabolic Heart Failure With Preserved Ejection In Mice.

Heart failure with preserved ejection fraction (HFpEF) represents a common clinical endpoint of cardiometabolic diseases which impair myocardial diastolic relaxation and/or stiffness. Although myocardial redox perturbations are known to accompany HFpEF, their contribution to its pathogenesis has not been clearly demonstrated. Therefore, our multi-cohort murine study sought to determine whether constitutive expression of NNT, a mitochondrial transhydrogenase that couples NADPH:NADP + to NADH:NAD + homeostasis, is required for the cardiometabolic manifestations of HFpEF in mice. Four cohorts of 12-week-old male and female mice with wild-type (NNT +/+ ) or mutant (NNT -/- ) NNT were supplied a combined high-fat and 0.5% N(ω)-nitro-L-arginine methyl ester (HFD-LNAME) diet for 9 weeks (n = 6-10). Although male NNT +/+ mice developed expected increases in body weight (23.2% Δ, P = 0.003), hypertension (24 ± 5 Δ mmHg, P = 0.02), impaired glucose tolerance ( P = 0.006), and reduced maximal treadmill running distance (-172 ± 73.1 Δ m, P = 0.006) following 9 weeks HFD-LNAME, male NNT -/- mice were protected against such cardiometabolic dysfunction. As previously shown, female mice failed to develop cardiometabolic dysfunction independent of NNT genotype. Cardiac phenotyping via echocardiography and invasive PV-loop analysis revealed increased E/e’ (42.8 vs. 21.5, P < 0.001) and E/A (2.3 vs 1.4, P = 0.007) ratios, diastolic stiffness (0.09 vs 0.04 mmHg/μL, P = 0.02), and myocardial fibrosis ( P = 0.02). Myocardial transcriptomic analysis via RNA-sequencing revealed robust unsupervised clustering of both genotypic and dietary groups, which ultimately showed disproportionate perturbations mitochondrial metabolic and redox signaling intermediate genes. Our search for putative transcriptional regulators identified NAD + deacetylase Sirt3 as an NNT-dependent oxidative response gene that appears to underlie cardiometabolic HFpEF. Taken together, these observations support that the loss of NNT protects against nitrosative stress-induced cardiac and metabolic consequences of HFD-LNAME in mice, thus highlighting a novel therapeutic avenue for HFpEF.