Effects Of Pioglitazone On Proliferation And Collagen Synthesis In Cardiac Fibroblasts Of Spontaneous Hypertesion Rat (SHR) And Their Relations To Cardiac Remodeling

Background Left ventricular hypertrophy is regarded as a strong independent risk factor for the morbidity and mortality of essential hypertension. Nowdays the reversal of left ventricular hypertrophy is one of main targets for the treatment of essential hypertension. Besides cardiomyocytes hypertrophy, the pathological basis of left ventricular hypertrophy shows cardiac fibroblasts proliferation and excessive extracellular matrix protein accumulation, which leads to myocardial fibrosis. Hypertensive myocardial fibrosis has been shown to facilitate ventricular dysfunction, diminished coronary reserve and ventricular arrhythmias that adversely affect the clinical outcome of hypertensive patients. Therefore, matrix remodeling is pathologic basis of myocardial remodeling. We should study matrix remodeling carefully and take effective measures to inhibit or promote matrix remodeling, they may give us a possible way to improve cardiovascular function.Nowadays, the acknowledged concept that the essential hypertension are strongly correlated with insulin resistance. The metabolic syndrome was defined as glucose intolerance, hypertension,low high-density lipoprotein cholesterol and hypertriglyceridemia. Some believed insulin resistance played an important role in the aetiology of essential hypertension.Pioglitazone hydrochloride, the thiazolidinediones which are novel insulin-sensitizing agents,as the high affinity ligands for peroxisome proliferator-activated receptor y (PPARy,also as pecific PPARr agonists), has been demonstrated to improve insulin sensitivity so as to attenuate insulin resistance. Recently, studies about thiazolidinediones found that they have the powerful cardiovascular protection, such as attenuate vascular smooth muscle cells prolifertion inhibit pathological cardiac hypertrophy regulate endothelial cell functions ameliorate intriacylglycerol and cholesterol metabolism and reduce plasminogen activator inhibitor-1, and also retard the process of atherosclerosis. Till now, the role of PIO in the pathogenesis of left ventricular hypertrophy associated with hypertension has not been clearly defined. PIO has been proved to attenuate vascular smooth muscle cells prolifertion and inhibit pathological cardiac hypertrophy; however, whether PIO is effective in cardiac interstitium is still obscure.The aim of this study was to evaluate the antiproliferative effects of PIO on cardiac fibroblasts isolated from SHR and Wistar rat, and its relationship with nitric oxide synthase-nitric oxide system activity and the expressing of NF- k B protein. Furthermore,this studies also want to investigate the effects of PIO on preventing myocardium remodeling so as to provide a valuable theory and. a novel pharmacological strategy for treatment of essential hypertension and find a new way for application of PIO.Methods Isolated and cultured CFs of SHR and Wistar rats wereused as experiment model. (1) CFs number was measured by MTT assay. FCM determine cell cycle. Collagen content of CFs culture supernatant was estimated by hydroxyproline chromatogragy. We want to investigate the effects of PIO with different concentration and time on proliferation and collagen synthesis of SHR CFs and their relations to cardiac remodeling. (2)Nitrate enzyme reverting method and spectrophotometer were also adopted to estimated the content of NO and activity of NOS in CFs of SHR with or without PIO. We also want to investigate the effects of PIO on the changing of NOS-NO system activity. (3) Using immunohistochemistry, we investigate the effects of PIO on the expressing of NF- k B protein.Results The results showed that:(1)PIO can inhabit proliferation of CFs from SHR in a concentration-dependent manner with different concentrations of PIO. A490 absorbant value of CFs treated by PIO for 24 hours (1X10-7 1X10-6 5 X 10-6 1X 10-5 mol/L were: SHR 0.19+0. 01 0.18+0. 01 0.16 + 0.01 0.16 + 0.02; Wistar0. 21 + 0. 01 0.19 + 0. 01 0.18 + 0. 01 0.17 + 0. 01) were significantly lower than those of corresponding control groups (0. 22 + 0. 0...