Chronic Administration of the Nitroxyl Donor 1-Nitrosocyclo Hexyl Acetate Limits Left Ventricular Diastolic Dysfunction in a Mouse Model of Diabetes Mellitus In Vivo

Abstract

Background-Nitroxyl (HNO), a redox congener of nitric oxide (NO•), is a novel regulator of cardiovascular function, combining concomitant positive inotropic, lusitropic, and vasodilator properties. Moreover, HNO exhibits myocardial antihypertrophic and superoxide-suppressing actions. Despite these favorable actions, the impact of chronic HNO administration has yet to be reported in the context of cardiomyopathy. Diabetic cardiomyopathy is characterized by early diastolic dysfunction and adverse left ventricular (LV) structural remodeling, with LV superoxide generation playing a major causal role. We tested the hypothesis that the HNO donor 1-nitrosocyclohexylacetate (1-NCA) limits cardiomyocyte hypertrophy and LV diastolic dysfunction in a mouse model of diabetes mellitus in vivo. Methods and Results-Diabetes mellitus was induced in male FVB/N mice using streptozotocin. After 4 weeks, diabetic and nondiabetic mice were allocated to 1-NCA therapy (83 mg/kg per day IP) or vehicle and followed up for a further 4 weeks. Diabetes mellitus-induced LV diastolic dysfunction was evident on echocardiography-derived E and A wave velocities, E:A ratio, deceleration, and isovolumic relaxation times; LV systolic function was preserved. Increased LV cardiomyocyte size, hypertrophic and profibrotic gene expression, and upregulation of LV superoxide were also evident. These characteristics of diabetic cardiomyopathy were largely prevented by 1-NCA treatment. Selectivity of 1-NCA as an HNO donor was demonstrated by sensitivity of acute 1-NCA to L-cysteine but not to hydroxocobalamin in the normal rat heart ex vivo. Conclusions-Our studies provide the first evidence that HNO donors may represent a promising strategy for treatment of diabetic cardiomyopathy and implies therapeutic efficacy in settings of chronic heart failure. (Circ Heart Fail. 2015;8:572-581.

Serelaxin treatment reverses vascular dysfunction and left ventricular hypertrophy in a mouse model of Type 1 diabetes

“…Overall, there was hence no nett impact of serelaxin on heart weight at study endpoint in diabetic mice. These observations of favourable effects of serelaxin on the phenotype of the diabetic heart, without gross changes in heart weight index, are consistent with other cardioprotective interventions in the diabetic heart, including nitroxyl donors17, and both the endogenous antioxidant coenzyme Q10 and the “gold standard” therapy for the cardiovascular complications of diabetes, an angiotensin-converting-enzyme (ACE) inhibitor16.…”

“…LV hypertrophy often precedes the morphological manifestation of diabetic cardiomyopathy, as evidenced by excess LV mass, which subsequently leads to a stiffer ventricle13. Indeed, we have previously demonstrated an increase in cardiomyocyte size that is associated with an upregulation of anti-hypertrophic genes such as natriuretic peptide type B (BNP), β-myosin heavy chain and atria natriuretic peptide (ANP) in the LV of diabetic animals14151617.…”

Mast Cell Inhibition Attenuates Cardiac Remodeling and Diastolic Dysfunction in Middle-aged, Ovariectomized Fischer 344 × Brown Norway Rats

“…1,2,5 Various animal models have been used in the study of LVDD, including the mRen2.Lewis rats, 9,10 deoxycorticosterone acetate-hypertensive rats, 30 spontaneously hypertensive rats (SHR), 31 streptozotocin and a high-fat diet-induced diabetic rats and mice, 32,33 lipopolysaccharide-induced high inflammation and LVDD, 34 and aortocaval fistula-induced volume overload model. 35 However, all these animal models are pathological models and may not reflect the biological conditions of LVDD that exist in healthy, aging women after the cessation of ovarian estrogen production.…”

Recent advances in the chemical biology of nitroxyl (HNO) detection and generation

“…108,109 Recent work shows these compounds limit left ventricular diastolic dysfunction in a mouse model of diabetes suggesting the possibility of long-term use of HNO donors in chronic diseases. 110 …”