Chronic administration of the nitroxyl donor 1-nitrosocyclo hexyl acetate limits left ventricular diastolic dysfunction in a mouse model of diabetes mellitus in vivo.
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.


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.
From the Departments of Heart Failure Pharmacology (N.C., Y.G.W., S.R., C.Q., R.H.R.) and Experimental Cardiology (H.K. X.J.D.), Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia; and Departments of Pharmacology (Y.G.W., B.K.K.-H.) and Medicine (K.H., X.-J.D., R.H.R.), Monash University, Clayton, Victoria, Australia.
Nga
N
Cao
From the Departments of Heart Failure Pharmacology (N.C., Y.G.W., S.R., C.Q., R.H.R.) and Experimental Cardiology (H.K. X.J.D.), Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia; and Departments of Pharmacology (Y.G.W., B.K.K.-H.) and Medicine (K.H., X.-J.D., R.H.R.), Monash University, Clayton, Victoria, Australia.
Yung George
YG
Wong
From the Departments of Heart Failure Pharmacology (N.C., Y.G.W., S.R., C.Q., R.H.R.) and Experimental Cardiology (H.K. X.J.D.), Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia; and Departments of Pharmacology (Y.G.W., B.K.K.-H.) and Medicine (K.H., X.-J.D., R.H.R.), Monash University, Clayton, Victoria, Australia.
Sarah
S
Rosli
From the Departments of Heart Failure Pharmacology (N.C., Y.G.W., S.R., C.Q., R.H.R.) and Experimental Cardiology (H.K. X.J.D.), Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia; and Departments of Pharmacology (Y.G.W., B.K.K.-H.) and Medicine (K.H., X.-J.D., R.H.R.), Monash University, Clayton, Victoria, Australia.
Helen
H
Kiriazis
From the Departments of Heart Failure Pharmacology (N.C., Y.G.W., S.R., C.Q., R.H.R.) and Experimental Cardiology (H.K. X.J.D.), Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia; and Departments of Pharmacology (Y.G.W., B.K.K.-H.) and Medicine (K.H., X.-J.D., R.H.R.), Monash University, Clayton, Victoria, Australia.
Karina
K
Huynh
From the Departments of Heart Failure Pharmacology (N.C., Y.G.W., S.R., C.Q., R.H.R.) and Experimental Cardiology (H.K. X.J.D.), Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia; and Departments of Pharmacology (Y.G.W., B.K.K.-H.) and Medicine (K.H., X.-J.D., R.H.R.), Monash University, Clayton, Victoria, Australia.
Chengxue
C
Qin
From the Departments of Heart Failure Pharmacology (N.C., Y.G.W., S.R., C.Q., R.H.R.) and Experimental Cardiology (H.K. X.J.D.), Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia; and Departments of Pharmacology (Y.G.W., B.K.K.-H.) and Medicine (K.H., X.-J.D., R.H.R.), Monash University, Clayton, Victoria, Australia.
Xiao-Jun
XJ
Du
From the Departments of Heart Failure Pharmacology (N.C., Y.G.W., S.R., C.Q., R.H.R.) and Experimental Cardiology (H.K. X.J.D.), Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia; and Departments of Pharmacology (Y.G.W., B.K.K.-H.) and Medicine (K.H., X.-J.D., R.H.R.), Monash University, Clayton, Victoria, Australia.
Barbara K
BK
Kemp-Harper
From the Departments of Heart Failure Pharmacology (N.C., Y.G.W., S.R., C.Q., R.H.R.) and Experimental Cardiology (H.K. X.J.D.), Baker IDI Heart & Diabetes Institute, Melbourne, Victoria, Australia; and Departments of Pharmacology (Y.G.W., B.K.K.-H.) and Medicine (K.H., X.-J.D., R.H.R.), Monash University, Clayton, Victoria, Australia. rebecca.ritchie@bakeridi.edu.au.
Rebecca H
RH
Ritchie
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D058065:Diabetic Cardiomyopathies / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D003971:Diastole; D004305:Dose-Response Relationship, Drug; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects
C554428:1-nitrosocyclohexyl acetate; D000085:Acetates; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D013481:Superoxides
cardiomyopathies; diabetes mellitus; diastolic heart failure; left ventricular hypertrophy; nitrates