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Dysregulation of matrix metalloproteinases and their tissue inhibitors is related to abnormality of left ventricular geometry and function in streptozotocin‐induced diabetic minipigs
Author(s) -
Lu Lin,
Zhang Qi,
Pu Li Jin,
Peng Wen Hui,
Yan Xiao Xiang,
Wang Lin Jie,
Chen Qiu Jing,
Zhu Zheng Bing,
Michel JeanBaptiste,
Shen Wei Feng
Publication year - 2008
Publication title -
international journal of experimental pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.671
H-Index - 72
eISSN - 1365-2613
pISSN - 0959-9673
DOI - 10.1111/j.1365-2613.2008.00579.x
Subject(s) - medicine , ventricle , endocrinology , diabetes mellitus , streptozotocin , matrix metalloproteinase , plasminogen activator , plasminogen activator inhibitor 1
Summary This study aimed to characterize matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in relation to changes in left ventricle (LV) geometry and function in a porcine model with streptozotocin (STZ)‐induced diabetes. In 15 Chinese Guizhou minipigs with STZ‐induced diabetes (diabetic group) and 15 age‐matched normal controls (control group), Doppler tissue imaging was performed at 6 months of diabetes. Serum MMP‐2, ‐9, TIMP‐1, ‐4 and B‐type natriuretic peptide (BNP) were determined. Expression of MMPs, TIMPs, urokinase type‐plasminogen activator (uPA), its receptor (uPAR) and plasminogen activator inhibitor‐1 (PAI‐1) in aortic intima and LV myocardium was evaluated, with gelatinolytic activities of tissue MMP‐2, ‐9 accessed by zymography. Left ventricle end‐diastolic septum thickness ( P < 0.05) and mass ( P < 0.05) were increased, whereas peak systolic mitral annulus velocity (Sm, P < 0.001), LV systolic ( P = 0.01) and diastolic strain ( P < 0.001) were significantly decreased in diabetic group than in controls. Diabetic group showed higher expression of TIMP‐1, ‐4 in aortic intima and LV myocardium ( P < 0.01 or P < 0.05), with increased collagen content and elevated serum BNP level ( P = 0.004) and lower gelatinolytic activities of tissue MMP‐2, ‐9 (all P < 0.05). Semi‐quantitative RT‐PCR of those diabetic tissues revealed elevated mRNA levels of major TIMPs, uPA, uPAR and PAI‐1. Reduction of serum MMP‐2 and ‐9 levels was observed in diabetic group vs. control group (both P < 0.05). This study features elevated levels of TIMP‐1, ‐4, uPA, uPAR and PAI‐1, and decreased activities of MMP‐2, ‐9 in aorta and myocardium in STZ‐induced diabetic minipigs, indicating that MMP–TIMP dysregulation is associated with LV hypertrophy, cardiac dysfunction and increased cardiovascular fibrosis in diabetes.