title: Heart angiotensin II-induced cardiomyocyte hypertrophy suppresses coronary angiogenesis and progresses diabetic cardiomyopathy.
abstract: 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.
authors.affiliation: Divisions of Nephrology, Department of Internal Medicine, Jichi Medical University, Yakushiji, Shimotsuke, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Masuda
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Muto
authors.forename: Genro
authors.initials: G
authors.lastname: Fujisawa
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Iwazu
authors.forename: Mariko
authors.initials: M
authors.lastname: Kimura
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Nonaka-Sarukawa
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Sasaki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Masami
authors.initials: M
authors.lastname: Shinohara
authors.forename: Takashi
authors.initials: T
authors.lastname: Murakami
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Shimada
authors.forename: Eiji
authors.initials: E
authors.lastname: Kobayashi
authors.forename: Eiji
authors.initials: E
authors.lastname: Kusano
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology*; D058065:Diabetic Cardiomyopathies / Q000209:etiology / Q000503:physiopathology*; D004195:Disease Models, Animal; D006984:Hypertrophy / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D000068557:Olmesartan Medoxomil; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology; D019700:Thrombospondin 1 / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
chemical_list: D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D013777:Tetrazoles; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D000068557:Olmesartan Medoxomil