title: Dysregulation of matrix metalloproteinases and their tissue inhibitors is related to abnormality of left ventricular geometry and function in streptozotocin-induced diabetic minipigs.
abstract: 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.
authors.affiliation: Department of Cardiology, Rui Jin Hospital, Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Li Jin
authors.initials: LJ
authors.lastname: Pu
authors.forename: Wen Hui
authors.initials: WH
authors.lastname: Peng
authors.forename: Xiao Xiang
authors.initials: XX
authors.lastname: Yan
authors.forename: Lin Jie
authors.initials: LJ
authors.lastname: Wang
authors.forename: Qiu Jing
authors.initials: QJ
authors.lastname: Chen
authors.forename: Zheng Bing
authors.initials: ZB
authors.lastname: Zhu
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Michel
authors.forename: Wei Feng
authors.initials: WF
authors.lastname: Shen
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D020097:Natriuretic Peptide, Brain / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics; D013552:Swine; D013556:Swine, Miniature; D046509:Tissue Culture Techniques; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D017539:Tunica Intima / Q000378:metabolism; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D020097:Natriuretic Peptide, Brain; D020782:Matrix Metalloproteinases