scholarly journals S-Nitrosylation of Histone Deacetylase 2 by Neuronal Nitric Oxide Synthase as a Mechanism of Diastolic Dysfunction

Circulation ◽  
2021 ◽  
Author(s):  
Somy Yoon ◽  
Mira Kim ◽  
Hangyeol Lee ◽  
Gaeun Kang ◽  
Kenneth Bedi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Nitric Oxide Synthase ◽  
Diastolic Dysfunction ◽  
Diastolic Function ◽  
Histone Deacetylase ◽  
Neuronal Nitric Oxide Synthase ◽  
Histone Deacetylase 2 ◽  
Oxide Synthase

Background: Although the clinical importance of heart failure with preserved ejection fraction (HFpEF) has been extensively explored, most therapeutic regimens, including nitric oxide (NO) donors, lack therapeutic benefit. Although the clinical characteristics of HFpEF are somewhat heterogeneous, diastolic dysfunction (DD) is one of the most important features. Here we report that neuronal nitric oxide synthase (nNOS) induces DD by S-nitrosylation of histone deacetylase 2 (HDAC2). Methods: Two animal models of DD—SAUNA (SAlty drinking water/Unilateral Nephrectomy/Aldosterone) and mild transverse aortic constriction (mTAC) mice— as well as human heart samples from left ventricular hypertrophy (LVH) patients were used. Genetically modified mice that were either nNOS-ablated or HDAC2 S-nitrosylation-resistant were also challenged. N(ω)-propyl-L-arginine (NPLA), an nNOS selective inhibitor, and dimethyl fumarate (DMF), an NRF2 inducer, were used. Molecular events were further checked in human left ventricle specimens. Results: SAUNA or mTAC stress impaired diastolic function and exercise tolerance without overt systolic failure. Among the post-translational modifications tested, S-nitrosylation was most dramatically increased in both models. Utilizing heart samples from both mice and humans, we observed increases in nNOS expression and NO production. NPLA alleviated the development of DD in vivo . Similarly, nNOS knock out mice were resistant to SAUNA stress. nNOS-induced S-nitrosylation of HDAC2 was relayed by transnitrosylation of GAPDH. HDAC2 S-nitrosylation was confirmed in both DD mouse and human LVH. S-Nitrosylation of HDAC2 took place at C262 and C274. When DD was induced, HDAC2 S-nitrosylation was detected in wild type mouse, but not in HDAC2 knock-in mouse heart that expressed HDAC2 C262A/C274A. In addition, HDAC2 C262A/C274A mice maintained normal diastolic function under DD stimuli. Gene delivery with AAV9-NRF2, a putative denitrosylase of HDAC2, or pharmacologic intervention by DMF successfully induced HDAC2 denitrosylation and mitigated DD in vivo . Conclusions: Our observations are the first to demonstrate a new mechanism underlying DD pathophysiology. Our results provide theoretical and experimental evidence to explain the ineffectiveness of conventional NO-enhancement trials for improving DD with heart failure symptoms. More importantly, our results suggest that reduction of NO or denitrosylation of HDAC2 may provide a new therapeutic platform for the treatment of refractory HFpEF.

scholarly journals Cardiac nitric oxide synthase 1 worsens heart failure with preserved ejection fraction through S-nitrosylation of histone deacetylase 2

2019 ◽  
Author(s):  
Somy Yoon ◽  
Mira Kim ◽  
Hangyeol Lee ◽  
Gaeun Kang ◽  
Kwang-Il Nam ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Nitric Oxide Synthase ◽  
Ejection Fraction ◽  
Histone Deacetylase ◽  
Clinical Importance ◽  
No Production ◽  
Preserved Ejection Fraction ◽  
Histone Deacetylase 2 ◽  
Oxide Synthase

AbstractAlthough 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.

Abstract 085: CHIP: E3 Ubiquitin Ligase Mediates Proteasomal Degradation of Neuronal Nitric Oxide Synthase in the Paraventricular Nucleus of Rats with Heart Failure

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Neeru M Sharma ◽  
Kenichi Katsurada ◽  
Xuefei Liu ◽  
Kaushik P Patel
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Nitric Oxide Synthase ◽  
Paraventricular Nucleus ◽  
Ubiquitin Ligase ◽  
Protein A ◽  
Neuronal Nitric Oxide Synthase ◽  
Proteasomal Degradation ◽  
Oxide Synthase

The exaggerated sympathetic drive is a characteristic of heart failure (HF) due to reduced neuronal nitric oxide synthase (nNOS) within the paraventricular nucleus (PVN). Previously we have shown that there were increased accumulation of nNOS-ubiquitin (nNOS-Ub) conjugates in the PVN of rats with HF (1.0±0.05 Sham vs. 1.29±0.06 HF) due to the increased levels of PIN (a protein inhibitor of nNOS, known to dissociate nNOS dimers into monomers) (0.76±0.10 Sham vs. 1.12±0.09 HF) and decreased levels of tetrahydrobiopterin (BH4): a cofactor required for stabilization of nNOS dimers (0.62±0.02 Sham vs. 0.44±0.03 HF). We also showed that there is blunted nitric oxide-mediated inhibition of sympathetic tone via the PVN in HF. Here we examined whether CHIP(C-terminus of Hsp70 -interacting protein), a chaperone-dependent E3 ubiquitin-protein isopeptide ligase known to ubiquitylate Hsp90-chaperoned proteins could act as an ubiquitin ligase for nNOS in the PVN. Immunofluorescence studies revealed colocalization of nNOS and CHIP in the PVN indicating their possible interaction. CHIP expression was increased by 50% in the PVN of rats with HF(0.96±0.08 Sham vs.1.44±0.10* HF). It is shown that Hsp90 protects nNOS from ubiquitination while Hsp70 promotes the ubiquitination and degradation. We observed significant upregulation of Hsp70 (0.49±0.03 Sham vs. 0.65±0.02* HF) with a trend toward the decrease in Hsp90 expression (0.90±0.07 Sham vs. 0.71±0.06 HF). The opposing effects of the two chaperones could account for the increased CHIP-mediated ubiquitination and degradation of dysfunctional nNOS monomers in the PVN of rats with HF. Furthermore, neuronal NG108-15 cell line transfected with the pCMV3-CHIP-GFP spark (CHIP overexpression plasmid) showed approximately 74% increase in CHIP with concomitant 49% decrease in nNOS expression. In vitro ubiquitination assay in NG108 cells transfected with pCMV-(HA-Ub) 8 and pCMV3-CHIP-GFP spark plasmid reveal increased HA-Ub-nNOS conjugates (1.13 ± 0.09 Scramble vs. 1.65 ± 0.12* CHIP plasmid). Taken together, our results identify CHIP as an E3 ligase for ubiquitination of dysfunctional nNOS and CHIP expression is augmented during HF leading to increased proteasomal degradation of nNOS in the PVN.

Decreased gene expression of neuronal nitric oxide synthase in hypothalamus and brainstem of rats in heart failure

1996 ◽  
Vol 734 (1-2) ◽  
pp. 109-115 ◽  
Author(s):  
Kaushik. P. Pate ◽  
Kun Zhang ◽  
Irving H. Zucker ◽  
Teresa L. Krukoff
Keyword(s):  
Gene Expression ◽  
Nitric Oxide ◽  
Heart Failure ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Oxide Synthase

scholarly journals Synthesis and enzymatic evaluation of 2- and 4-aminothiazole-based inhibitors of neuronal nitric oxide synthase

2009 ◽  
Vol 5 ◽  
Author(s):  
Graham R Lawton ◽  
Haitao Ji ◽  
Pavel Martásek ◽  
Linda J Roman ◽  
Richard B Silverman
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Blood Brain Barrier ◽  
Neuronal Nitric Oxide Synthase ◽  
Lead Compound ◽  
Selective Inhibitors ◽  
Net Charge ◽  
In Vivo Efficacy ◽  
Oxide Synthase

Highly potent and selective inhibitors of neuronal nitric oxide synthase (nNOS) possessing a 2-aminopyridine group were recently designed and synthesized in our laboratory and were shown to have significant in vivo efficacy. In this work, analogs of our lead compound possessing 2- and 4-aminothiazole rings in place of the aminopyridine were synthesized. The less basic aminothiazole rings will be less protonated at physiological pH than the aminopyridine ring, and so the molecule will carry a lower net charge. This could lead to an increased ability to cross the blood-brain barrier thereby increasing the in vivo potency of these compounds. The 2-aminothiazole-based compound was less potent than the 2-aminopyridine-based analogue. 4-Aminothiazoles were unstable in water, undergoing tautomerization and hydrolysis to give inactive thiazolones.

scholarly journals Role of Myocardial Neuronal Nitric Oxide Synthase–Derived Nitric Oxide in β-Adrenergic Hyporesponsiveness After Myocardial Infarction–Induced Heart Failure in Rat

Circulation ◽  
2004 ◽  
Vol 110 (16) ◽  
pp. 2368-2375 ◽  
Author(s):  
Jennifer K. Bendall ◽  
Thibaud Damy ◽  
Philippe Ratajczak ◽  
Xavier Loyer ◽  
Virginie Monceau ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Oxide Synthase
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