The Level Of TGF-β1,PI3K,eNOS,NO From Myocardial Tissue Of Spontaneously Hypertensive Rats, And The Influence After Rosuvastatin Intervention

Objective:Hypertension is a common and frequently-occurring disease that can result in damage of organs and systems of the body. myocardial hypertrophy is one of the damages. it is an adaptive response to pressure and volume overload. long-persistent overpressure could lead to maladaptive even to trigger the development of heart failure.myocardial hypertrophy is the effective predetermination of morbidity and mortality independent of blood pressure level and other cardiovascular risk factors. the patients with left ventricular hypertrophy(LVH) that is diagnosised by electrocardiogram have hight risk,the risk is six times than those without LVH and diseases mortality increase 45﹪in the patients with LVH.Many experiments demonstrate that transforming growth factor-β₁(TGF-β₁)participates in the pathopoiesia process of cardiovascular diseases and aslo has crucial action in myocardial hypertrophy. TGF-β₁ is multifunction cytokine. it combines receptor and regulates many signaling pathways in cell. phosphoinositie3-kinase (PI3K) is the important downstream substrates of TGF-β₁ signaling, PI3K activates downstream substrates and can influence many functions. PI3K singaling pathway is important for the heart physiological growth and inhibition of pathological hypertrophy. many researchs show eNOS is one downstream substrates of PI3K, activited PI3K enhances eNOS and increases NO via catalyzing L-Arg so that protects cardiovascular. PI3K can protect vascular endothelial cell,relax blood vessel and resist myocardial hypertrophy through up-regulating eNOS/NO. TGF-β₁ can regulate PI3K expression with direct or in direct way.it suppresses PI3K expression in some pathophysiological progress and cell. it expresses abnormally in myocardial hypertrophy and influences PI3K expression, eNOS/ NO production and the protective action.Many factors involve in the occurrence,development of the myocardial hypertrophy. besides controlling blood pressure, we should aslo pay attation to regulations of moleculars. a large of clinical trials demonstrate that statin drugs( HMG-COA reductase inhibitor) besides have lipid-lowering role,statin could protect against stroke,ischemia-reperfusion injury in heart and vascular inflammatory response in normocholesterolemic animals.The experiment becomes conscious of the relation between TGF-β₁ signling pathway and myocardial hypertrophy through testing the changes of TGF-β₁, PI3K, eNOS, NO in cardiac muscle of SHR. to investigate the influence and possible mechanism to myocardial hypertrophy and relationship, different doses of rosuvastatin were used.Methods: In this research, eight Wistar-Kyoto rats(WKY)were regarded as normal group(group N),twenty-four SHR were randomly separated into group T1(rosuvastatin 3.125mg/(kg.d)group),group T2(rosuvastatin 6.25 mg/kg.d)group)and group H (hypertension control group). each group contents eight male rats, which were clean, 15-16 weeks old and weight 280-300g. the weight has no statistically differences among the groups(p>0.05). the systolic blood pressure has distinct difference between group N and SHR groups(p<0.05),but there were no statistically differences among the SHR groups .After two weeks free-running time in entironment, they were raised at 22±2℃and free feeded food and water. group T1 and group T2 were dealed with rosuvastatin3.125mg/(kg.d)and 6.25 mg/(kg.d)adding one millilitre distilled water, group N and group H was dealed with one millilitre distilled water.after eight weeks processing,taked the SBPand the weight and then killed all rats and operated on chest, the expressions of TGF-β₁ in rats myocardial tissue was determined by RT-PCR, the expression of PI3K was determined by Immunohistochemical and the contents of eNOS,NO by colorimetry. All datas were puted into SPSS13.0 statistics analysis software and noted as mean±standard deviation(x|ˉ±s).first testing normality and homogeneity and then worked out results with one-way classification, we used SNK-q to compare the differences among groups. P<0.05 shows statistical significance.Results: 1 The expression of TGF-β₁ in cardiac muscular tissue in group H(2.78±0.06)increased obviously compared with that in group N(0.88±0.02)(p<0.05). the expression of TGF-β₁ in group T1(1.76±0.04)and group T2(1.19±0.05)decreased apparently contrasted with that in group H(p<0.05). there were statistical significance between the treated groups(p<0.05).2 The expression of PI3K in cardiac muscular tissue in group H(2.16±0.07)decreased obviously compared with that in group N(5.87±0.10)(p<0.05). the expression of PI3K in group T1(4.08±0.07)and group T2(5.10±0.12)increased apparently contrasted with that in group H(p<0.05). there were statistical significance between the treated groups(p<0.05).3 The contents of eNOS in cardiac muscular tissue reduced in group H( 0.31±0.02 ) ,it lowered apparently compared with that in group N(0.67±0.03)(p<0.05).the contents in T1(0.39±0.03)and group T2(0.49±0.04)elevated obviously compared with that in group H(p<0.05). there were statistical significance between the treated groups(p<0.05).4 The contents of NO in cardiac muscular tissue in group H(0.80±0.02)lowered apparently contrasted with that in group N(1.37±0.04)(p<0.05).the contents in group T1(0.98±0.04)and group T2(1.13±0.03)elevated obviously contrasted with that in group H(p<0.05).there were statistical significance between the treated groups(p<0.05).5 The cardiac weight in group H(1445.46±31.47) increased higher than that in group N(1261.05±19.23)(p<0.05).group T1(1367.85±17.95),group T2(1267.01±24.89)of that decreased lower than in group H(p<0.05). there were statistical significance between the treated groups(p<0.05).6 The left ventricular cardiac weight in group H(1121.15±28.68)increased obviously higher than that in group N(739.78±22.16)(p<0.05).group T1(935.73±18.68), group T2(801.69±9.98)of that decreased apparently lower than that in group H. (p<0.05) there were statistical significance between the treated groups(p<0.05). 7 The left ventricular mass index in group H(3.45±0.05)increased obviously compared with that in group N(2.25±0.07)(p<0.05). that in group T1(2.90±0.06)and group T2(2.52±0.06)decreased apparently contrasted with that in group H(p<0.05). there were statistical significance between the treated groups(p<0.05).8 The cardiomyocye diameter in group H(19.47±0.57)was obviously thicker than the width in group N(13.78±0.39)(p<0.05).that in group T1(17.92±0.41)and group T2(16.29±0.29)were apparently thinner than that in group H(p<0.05). there were statistical significance between the treated groups(p<0.05).9 The weights were no statistical significances from each group(p>0.05).systolic blood pressure(SBP)of group H(193.38±4.53), group T1(198.00±4.72)and group T2(189.63±4.44)elevated markedly compared with that in group N(112.88±3.22)before treated with rosuvastatin. they have statistical significances between group N and the other SHR groups(p<0.05),there were no significantly differences among the SHR groups(p>0.05). SBP of group H(205.50±4.11)and group N(114.15±3.37)were mild rise after eight weeks processed with rosuvastatin, SBP of group T1(196.88±4.35),group T2(184.75±3.99)has a little lower,but it was no statistical significance(p>0.05). SBP of group T2 decreased contrasted with group H,it has statistical significance(p<0.05).Conclusions: 1 The expression of TGF-β₁ increases and the contents of PI3K,eNOS,NO decreases in SHR,we discoveres that TGF-β₁ signaling pathway has apparent changes in the occurrence and development of LVH, TGF-β₁/PI3K-eNOS pathway playes an important role in ventricular hypertrophy. 2 The study confirms that TGF-β₁ down-regulates PI3K,eNOS,NO and supresses expressing of cardiac protective factors.rosuvastatin can promotes the expression of TGF-β₁ and reduces the levels of PI3K,eNOS,NO in cardiac muscular tissue of SHR. it proves that rosuvastatin could improve myocardial performance. this effect may be related to regulating TGF-β₁ pathway through using rosuvastatin. 3 Rosuvastatin can bring down systolic blood pressure mildly in SHR.the action mechanisms probably relate to up-regulating PI3K- eNOS and NO. 4 Different doses of rosuvastatin can influence the levels of index that the changes show the drug has dose-dependent.