Role of S‐nitrosoglutathione reductase (GSNOR) Dysregulation and Nitrosative Stress in Heart Failure With Preserved Ejection Fraction

Abstract

Background Heart failure with preserved ejection fraction (HFpEF) is the most predominant form of heart failure in the United States. This multi‐system pathology results in a 5‐year mortality rate for which there are very few treatment options. The obese ZSF1 rat model has previously been shown to recapitulate much of the human phenotype including obesity, metabolic syndrome, diabetes, and hypertension. In this study, we investigated the complex and largely unknown role of abnormal nitric oxide signaling and nitrosative stress in the pathobiology of HFpEF. Materials and Methods Male ZSF1 rats and normotensive controls of Wistar Kyoto (WKY) background strain (n=7 each group) were studied at 10, 14 and 18 weeks of age to monitor disease progression and alterations in nitric oxide signaling. Cardiac protein nitrosylation (RxNO) was measured by chemiluminescence. Analysis of circulating plasma nitrite bioavailability was performed using high performance liquid chromatography. GSNOR, one of the enzymes that degrade nitrosothiols, mRNA expression was measured and plotted as relative fold difference to WKY expression in this model of cardiometabolic HFpEF. Results ZSF1 rats exhibited significantly increased cardiac protein nitrosylation as the HFpEF phenotype progressed from 10 to 18 weeks of age as compared to the WKY rat group. GSNOR mRNA expression was significantly decreased in the ZSF1 rat relative to the WKY at all time points. During the later 18‐week timepont, cardiac GSNOR activity was found to be decreased compared to that of the WKY. Circulating plasma nitrite, a measure of eNOS function, was decreased in the ZSF1 rat at 14 and 18 weeks compared to the WKY at subsequent aging timepoints. These data correlate to an increasing left ventricular end diastolic pressure (LVEDP) and decreased vascular relaxation as the ZSF1 animals age and develop more severe HFpEF disease pathology. Conclusion Our data suggests that nitric oxide signaling is dysregulated in the setting of HFpEF resulting in a significant increase in cardiac protein nitrosylation coupled with a reduction in circulating nitrite and NO signaling in the vasculature. Excessive cardiac nitrosative stress resulting in pathological myocardial signaling has been previously implicated as a driver of HFpEF. Reduced vascular nitrite bioavailability resulting in attenuated physiological NO signaling could account for the profound vascular dysfunction observed in HFpEF patients. Future studies are aimed at the further elucidation of the role of various NO storage pools in HFpEF.