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Abstract
BackgroundType 2 diabetes is frequently associated with co-morbidities, including hypertension. Here we investigated if hypertension is a critical factor in myocardial remodeling and the development of cardiac dysfunction in type 2 diabetic db/db mice.MethodsThereto, 14-wks-old male db/db mice and non-diabetic db/+ mice received vehicle or angiotensin II (AngII) for 4 wks to induce mild hypertension (n = 9–10 per group). Left ventricular (LV) function was assessed by serial echocardiography and during a dobutamine stress test. LV tissue was subjected to molecular and (immuno)histochemical analysis to assess effects on hypertrophy, fibrosis and inflammation.ResultsVehicle-treated diabetic mice neither displayed marked myocardial structural remodeling nor cardiac dysfunction. AngII-treatment did not affect body weight and fasting glucose levels, and induced a comparable increase in blood pressure in diabetic and control mice. Nonetheless, AngII-induced LV hypertrophy was significantly more pronounced in diabetic than in control mice as assessed by LV mass (increase +51% and +34%, respectively, p<0.01) and cardiomyocyte size (+53% and +31%, p<0.001). This was associated with enhanced LV mRNA expression of markers of hypertrophy and fibrosis and reduced activation of AMP-activated protein kinase (AMPK), while accumulation of Advanced Glycation End products (AGEs) and the expression levels of markers of inflammation were not altered. Moreover, AngII-treatment reduced LV fractional shortening and contractility in diabetic mice, but not in control mice.ConclusionsCollectively, the present findings indicate that type 2 diabetes in its early stage is not yet associated with adverse cardiac structural changes, but already renders the heart more susceptible to hypertension-induced hypertrophic remodeling.
Highlights
Diabetes, hypertension, dyslipidemia and obesity are independent risk factors for the development of cardiovascular disease, with hypertension being the most common risk factor [1,2]
In two previous studies we found no evidence of marked cardiac dysfunction and structural remodeling in two animals models of type 2 diabetes, namely in adult db/db mice and in senescent Zucker Diabetic Fatty (ZDF) rats [6,7]
General characteristics The diabetic db/db mice (DM) demonstrated significantly higher body weights and fasting blood glucose levels when compared with the non-diabetic, control (Cn) mice from the start (14 wks) till the end of the experimental period (18 wks) (Figure 1A and 1B)
Summary
Hypertension, dyslipidemia and obesity are independent risk factors for the development of cardiovascular disease, with hypertension being the most common risk factor [1,2]. In diabetic patients a clustering of risk factors commonly occurs which markedly increases the risk for the development of cardiovascular pathology. Both clinical and experimental studies suggested that diabetes by itself, i.e., in the absence of established hypertension or coronary artery disease, can already lead to abnormalities in cardiac function and structure. The latter condition is generally referred to as diabetic cardiomyopathy [3,4,5]. We investigated if hypertension is a critical factor in myocardial remodeling and the development of cardiac dysfunction in type 2 diabetic db/ db mice
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