To examine whether and how heart ANG II influences the coordination between cardiomyocyte
hypertrophy and coronary angiogenesis and contributes to the pathogenesis of
diabetic cardiomyopathy, we used Spontaneously Diabetic Torii (SDT) rats treated without and with
olmesartan medoxomil (an ANG II receptor blocker). In SDT rats, left ventricular (LV) ANG II, but not circulating ANG II, increased at 8 and 16 wk after diabetes onset. SDT rats developed LV
hypertrophy and diastolic dysfunction at 8 wk, followed by
LV systolic dysfunction at 16 wk, without
hypertension. The SDT rat LV exhibited cardiomyocyte
hypertrophy and increased
hypoxia-inducible factor-1α expression at 8 wk and to a greater degree at 16 wk and interstitial
fibrosis at 16 wk only. In SDT rats, coronary angiogenesis increased with enhanced capillary proliferation and upregulation of the
angiogenic factor VEGF at 8 wk but decreased
VEGF with enhanced capillary apoptosis and suppressed capillary proliferation despite the upregulation of
VEGF at 16 wk. In SDT rats, the phosphorylation of
VEGF receptor-2 increased at 8 wk alone, whereas the expression of the antiangiogenic factor thrombospondin-1 increased at 16 wk alone. All these events, except for
hyperglycemia or blood pressure, were reversed by
olmesartan medoxomil. These results suggest that LV ANG II in SDT rats at 8 and 16 wk induces cardiomyocyte
hypertrophy without affecting
hyperglycemia or blood pressure, which promotes and suppresses coronary angiogenesis, respectively, via
VEGF and thrombospondin-1 produced from hypertrophied cardiomyocytes under chronic
hypoxia. Thrombospondin-1 may play an important role in the progression of
diabetic cardiomyopathy in this model.