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Al Ali, Parekh, Qureshi, Jayaprakash, Adeghate, Howarth, and Adrian: Induced nitric oxide synthase and diabetic cardiomyopathy

Introduction: Nearly 80% of deaths associated with type 2 diabetes mellitus are attributed to cardiac complications. Diabetics tend to develop heart failure in the absence of risk factors such as hypertension and coronary artery disease. Nitric oxide (NO) is constitutively or inductively synthesized by nitric oxide synthase, which has three isoforms, endothelial (eNOS), neuronal (nNOS) and inducible (iNOS). eNOS has effects that include regulation of heart rate, contraction, diastolic relaxation and oxygen consumption. nNOS regulates the activity of the sarcoplasmic reticulum Ca2+ ATPase activator and the L-type Ca2+ channel. Both eNOS and nNOS are considered to be cardioprotective. In contrast, iNOS is induced by stress, including hyperglycaemia and oxidative stress, and causes nitration of skeletal proteins resulting in impairment of myofilament function. The high concentrations of NO produced also form peroxynitrite, an oxidant that causes tissue damage. Myocardial damage during ischaemia reperfusion in hyperglycaemia is abolished in iNOS-knockout mice, confirming the importance of iNOS in the development of cardiomyopathy.

Objectives: To investigate expression of nNOS and iNOS in two models of type 2 diabetes mellitus in rats.

Materials and methods: Expression of nNOS and iNOS mRNA were measured using fast real-time reverse transcription polymerase chain reaction in cardiac tissue from 8-month-old Goto–Kakizaki lean diabetic (GK) and Zucker diabetic fatty (ZDF) rats.

Results: Expression of nNOS was modestly, but significantly, increased in GK (P < 0.0001) and ZFD rats (P < 0.001). In contrast, iNOS expression was massively increased by 15-fold in GK rats (P < 0.0001).

Conclusions: Modest up-regulation of nNOS in both models suggests a cardioprotective effect. However, the massive up-regulation of expression of cardiac iNOS in type 2 diabetes mellitus supports the concept that this inducible isoform is involved in the development of diabetic cardiomyopathy.

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