Abstract
Disclosure: K. Islam: None. R. Islam: None. A. Draper: None. Background: Reduced nitric oxide (NO)bioavailability and decreased expression of mitochondrial transcription factor A (TFAM) occurs in the setting of heart failure (HF). TFAM promotes transcription of mitochondrial DNA, mitochondrial biogenesis, respiratory chain activity, and ATP synthesis. We investigated the effects of oral NaNO(2)therapy to increase NO in chronic HF following acute myocardial infarction and examined the effects of NaNO(2) on the activation of TFAM, mitophagy, and antioxidant signaling pathways. Methods: Male C57/BL6J mice underwent 60 minutes of myocardial ischemia (MI) induced by left coronary artery (LCA) occlusion followed by 4 weeks of reperfusion. NaNO(2) or saline vehicle (VEH)was administered at a dose of 165 µg/kg at reperfusion and then daily for 4weeks in the drinking water (100 mg/L). Left ventricular ejection fraction (LVEF) was determined at baseline and at 4 weeks of reperfusion. At 4 weeks of reperfusion myocardial tissue samples were collected and analyzed by RT-qPCR, immunoblot, oxidative stress assay, and protein sulfhydration assay. Results: NaNO(2) administration markedly preserved left ventricular ejection fraction (LVEF) and improved left ventricular diastolic and systolic dimensions at 4 weeks as compared to VEH. Mitochondrial antioxidant proteins, SOD2 (MnSOD), peroxiredoxin-3 (Prx-3) and thioredoxin 2 (TXN2) (p < 0.05) were markedly increased in NaNO(2)treated mice compared to VEH. Expression of mitophagic markers, p62 (p <0.05) and Map1lc3 (p < 0.05) were significantly increased in NaNO(2)treated HF mice as compared to VEH. Expression of mitochondrial quality control such as PINK1 and PARKIN2 were also markedly increased HF mice after treated with nitrite therapy as compared with VEH. Marked induction of sulfhydration of interferon regulator factor 1 (IRF-1) as well as upregulation of mitochondrial transcription factor A (TFAM) (p < 0.05) and suppression of DNA methyltransferase3a (Dnmt-3a) (p < 0.05) were observed in NaNO(2) treated ischemic HF mice as compared with VEH. Conclusions: Our results clearly demonstrate thatNaNO(2) therapy improves left ventricular function during ischemic HF through induction of antioxidant signaling, mitophagy, sulfhydration of IRF-1and TFAM resulting in increased mitochondrial biogenesis. Presentation: Thursday, June 15, 2023