Hypertension Is a Conditional Factor for the Development of Cardiac Hypertrophy in Type 2 Diabetic Mice

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.

Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities

“…Streptozotocin-induced insulin-dependent diabetes increased hypertensive myocardial fibrosis in rats [41]. Moreover, non-insulin dependent diabetes in mice increased myocardial susceptibility to hypertensive hypertrophy and fibrosis [42]. …”

Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities

“…Obesity may also augment the effects of other fibrogenic pathophysiologic conditions. In models of hypertensive fibrosis obesity increases myocardial hypertrophy and collagen deposition (30), (31). …”

P79 Ultrasonographic Characterization of the Db/Db Mouse, an Animal Model of Metabolic Abnormalities

“…Some interesting considerations can derive from our partially unexpected observations. A point of discussion is that, despite the higher weight, db/db animals show a reduced HR along with a low-performing myocardium both in diastolic and systolic phase: in fact, we did observe variations in E/A ratio, with absolute values greater than 2, thus suggesting the presence of a progressive diastolic dysfunction in these animals [25]. This effect can be attributed to the reduced physical activity [26] and an alteration in the cardiac autonomic balance of diabetic animals [27].…”

“…Furthermore, van Bilsen et al [25] associated the increased cardiac volumes only to the contemporary presence of sustained hypertension. Accordingly, we derived the aortic pulse pressure from the assessment of the local arterial stiffness, and we found an equivalent pulse pressure in the two groups, making questionable the role of the systemic pressure as major determinant of the after load and thus of LV mass in this animal model.…”

“…Therefore, we prefer to assess a raw estimate of the pulse pressure inverting the Bramwell-Hill equation. Moreover, our pulse pressure assessment was done under anesthesia, as all imaging procedures, and high levels of pressure are not expected in the db/db model [26,39] except when additional specific hits are included in the study design [25].…”