title: Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin-angiotensin system in hypertensive rats.
abstract: Diabetes mellitus (DM) is a major risk factor for heart failure, independent of coronary artery disease or hypertension (HT). Therefore, our study was designed to examine the mechanisms of DM-induced left ventricular (LV) diastolic dysfunction. In this study, we made five different 10-week treatment groups of Dahl salt-sensitive rats as follows: Control; a low-salt (0.5% NaCl) diet, HT; a high-salt (5% NaCl) diet, DM; a low-salt diet with streptozotocin (STZ) injection (30 mg kg(-1) i.p.), HT+DM; a high-salt diet with STZ injection, and the Olmesartan group; a high-salt diet with STZ treated with an angiotensin receptor blocker, olmesartan (1 mg kg(-1) day(-1)). Cardiac diastolic dysfunction with a preserved systolic function was noted in the HT group, and was most prominently noted in the HT+DM group, characterized by enhanced cardiac fibrosis, whereas the extent of HT and myocardial hypertrophy was comparable between the two groups. Myocardial expressions of collagen III, transforming growth factor-beta2, angiotensin-converting enzyme (ACE), angiotensin II type-1 receptor and myocardial oxidative stress (evaluated by 4-hydroxy-2-nonenal-modified protein) were mostly enhanced in the HT+DM group. Importantly, there was a positive correlation between the extent of diastolic dysfunction and that of myocardial ACE expression. All these cardiac abnormalities induced by DM and HT were ameliorated in the olmesartan group. These results indicate that DM accelerates diastolic dysfunction in hypertensive heart disease through activation of the renin-angiotensin system, with subsequent inflammatory and oxidative stresses and myocardial fibrosis, suggesting that an inhibition of the system is effective for the treatment of diastolic dysfunction in this combined disorder.
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Fukui
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fukumoto
authors.forename: Jun
authors.initials: J
authors.lastname: Suzuki
authors.forename: Kenya
authors.initials: K
authors.lastname: Saji
authors.forename: Jun
authors.initials: J
authors.lastname: Nawata
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shinozaki
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kagaya
authors.forename: Jun
authors.initials: J
authors.lastname: Watanabe
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D003920:Diabetes Mellitus / Q000473:pathology*; D004452:Echocardiography; D006439:Hemodynamics / Q000502:physiology; D006973:Hypertension / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009929:Organ Size / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D020303:Rats, Inbred Dahl; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000235:genetics; D012084:Renin-Angiotensin System / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000473:pathology*
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D044140:Receptor, Angiotensin, Type 1; D003094:Collagen