Cardiac nitric oxide synthase 1 worsens heart failure with preserved ejection fraction through S-nitrosylation of histone deacetylase 2
Yoon, S.; Kim, M.; Lee, H.; Kang, G.; Nam, K. I.; Kook, H.; Eom, G. H.
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Although the clinical importance of heart failure with preserved ejection fraction (HFpEF), which makes up half of heart failure, has been extensively explored, most therapeutic regimens, including nitric oxide (NO) donors, lack therapeutic benefit1-12. Here we report that neuronal nitric oxide synthase (nNOS, also known as NOS1) induces HFpEF by S-nitrosylation of histone deacetylase 2 (HDAC2). HFpEF animal models--SAUNA (SAlty drinking water/Unilateral Nephrectomy/Aldosterone)13,14 and mild transverse aortic constriction (TAC) mice14,15--showed increased nNOS expression and NO production, which resulted in the S-nitrosylation of HDAC2. HFpEF was alleviated in S-nitrosylation-dead HDAC2 knock-in mice. Pharmacologic intervention by either nNOS inhibition or HDAC2 denitrosylation attenuated HFpEF. Our observations are the first to demonstrate a completely new mechanistic aspect in HFpEF, which may provide a novel therapeutic approach to HFpEF. In addition, our results provide evidence for why conventional NO-enhancement trials have not been effective for improving HFpEF.
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