The Mechanism Of Atorvastatin Combined With Coenzyme Q10Inhibiting Ventricular Remodeling

It is known that ventricular remodeling is the pathological basis of heart failuredevelopment,and the non-infarced area of left ventricular remodeling plays animportant role in the pathogenic process of heart failure. After heart failure,energymetabolization obstacle may be ventricular enlargement and cardiac anomalies of themain reasons,which lead to myocardial remodeling,and then have a vicious circle ofmyocardial energy metabolism disorder and myocardial remodeling,which promotethe occurrence and development of heart failure. Therefore,regulating the cardiacenergy metabolism may become a new method in treatment of heartfailure.Mitochondria are the main organelles of energy generation and storage,mitochondria dysfunction is the core of myocardial metabolic disorders after heartfailure.Therefore,study of myocardial mitochondrial changes to reveal heart failureenergy metabolism and ventricular remodeling mechanisms has an importantsignificance.Uncoupling protein2(UCP2) is a transport protein and expression inmyocardium that is located in the mitochondrial inner membrane,involved in energymetabolism, apoptosis, the production of reactive oxygen species, furthermore,atherosclerosis, ischemia/reperfusion injury, obesity and type2diabetes.Currently,the studies of the UCP2expression in myocardium under physiological conditionmore,but the changes of UCP2expressions in non-infarced area after heart failure andthe relationship between the changes of UCP2expression in heart failure and innon-infarced area ventricular remodeling, at present have not beenreported.Coenzyme Q10is a fatsoluble organic quinones compound widely existing inthe living body, which is cellular respiration and metabolic activator as a hydrogencarrier for participating in the electron transfer process. Studies have shown thatmyocardial endogenous coenzyme Q10content in patients with congestive heartfailure is lower than the normal level, and through to the myocardial biopsy isindicated that the level of coenzyme Q10was positively correlated to the the degreeof heart failure patients,and exogenous coenzyme Q10also could significantlyimprove cardiac function. Atorvastatin is a hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor(statins)，widely used in coronary atherosclerosisheart disease to reduce blood lipids by inhibiting HMG-CoA reductase, which is thebiosynthesis of cholesterol in the liver,and increasing the number of low densitylipoprotein (LDL) receptor on liver cell surface,furthermore, increasing LDL uptakeand catabolism.But, more and more people concerned about the problems which arethe nonlipid effections of statins.An increasing number of clinical studies and animalexperiments show that statins and coenzyme Q10play an important role in thetreatment of cardiovascular diseases,which are the beneficial effects, especially inheart failure arouses more attentions. However it is unclear that statins combinedcoenzyme Q10effects on the non-infarced area of left ventricular remodeling byintervening energy metabolism and the expression changes of UCP2gene in heartfailure after acute myocardial infarction.Therefore, fistly, we explored the effects ofatorvastatin combined coenzyme Q10on energy metabolism and its related geneexpression changes of UCP2, and further probed into the non-infarced area of leftventricular remodeling in heart failure after acute myocardial infarction inrats.Secondly, we observed the effects of atorvastatin combined coenzyme Q10onAngII induced myocardial cells and cardiac fibroblasts energy metabolism relatedgene UCP2expression and myocardial remodeling in vitro. Our research observed theeffects and mechanisms of atorvastatin combined coenzyme Q10on energymetabolism and ventricular remodeling from whole and molecular level to cellular toprovide a theoretical basis in heart failure mechanisms,pathogenesis,treatment andfind more reasonable combination schemes to improves heart function.The mainresearch contents are as follows:Methods:Heart failure in female Wistar rat models were created by ligating left arterydescending(LAD) last6weeks. All the rats were drawed blood from the tail vein0.5ml after the surgery by ligating left artery descending in48hours,the levels ofcTnT were measured by ELISA to prove to build a successful animal model of acutemyocardial infarction,and it is significant that the Level cTnT of model group was3times for cTnT elevated levels of meaning.Survival of rats were randomly dividedinto sham operation group, model group, atorvastatin group and atorvastatin-coenzyme Q10group,6rats in each group.Continuous intragastric administration ofdrug over5weeks,we observed the changes of the non-infarced area of left ventricular on morphology of rat myocardium by using HE staining, Masson stainingand further electron microscopic detection; we also measured the changes ofhaemodynamics, such as left ventricular end-diastolic pressure (LVEDP),leftventricular systolic pressure(LVSP),+dp/dtmaxand-dp/dtmaxof left ventricularpressure;the whole heart hypertrophy index and left ventricular hypertrophy indexwere determined; in addition,the levels of BNP in plasma,the levels of Ang II inserum,the content of ATP in the non-infarced area of left ventricular,the activities ofsuccinodehydrogenase and cytochrome coxidase were quantified with ELISA;thecontents of MDA, lactate and free fatty acid,the activities of SOD,Na+-K+ATPase,Ca+-Mg+ATPase with chemical colorimetry were obtained.The expressions ofcol-I,col-III and UCP2mRNA was detected by RT-PCR in the non-infarced area ofleft ventricular,and the results of col-I/col-III were calculated.We also assayed theprotein expressions of col-I, col-III and UCP2by using immunohistochemical method,Furthermore, the protein expressions of UCP2in the non-infarced area of leftventricular by western bloting.Cardiomyocyte from neonatal rat were cultured in vitro,and researched theinhibition effects of atorvastatin and atorvastatin combined with coenzyme Q10oncardiomyocyte hypertrophy induced by angiotensin II.After24h,we examined themyocytes’ surface area,the content of total protein in Cardiomyocyte,furthermore, theprotein expressions of UCP2by western bloting assay. In addition, cardiac fibroblastsfrom neonatal rat were cultured in vitro,and researched the inhibition effects ofatorvastatin and atorvastatin combined with coenzyme Q10on on cardiac fibroblastsproliferation induced by angiotensin II.After24h, we analysed the quantities ofcardiac fibroblasts proliferation, the contents of hydroxyproline in the culturesupernatant,and the protein expressions of col-I and col-III by western bloting.Results:1、We succeeded in making heart failure rat models after myocardial infarction byligating LAD,compared with the sham operation group, cardiac enlargement, has notbeen able to maintain the normal geometry, ventricular chamber enlargement,occasionally left ventricular aneurysm in operation groups,and myocardial cellsarranged in disorder, myocardial interstitial fibrous tissue proliferation. Furthermore,hemodynamic changes,such asLVEDP were increased,LVSP and±dp/dtmax reduced.compared with the operation group.Atorvastatin group heart could basically maintain the normal shape, and reduced the degree of ventricular dilation; myocardial cellswere arranged in order, the degree of interstitial fibrosis decreased myocardial.2、Atorvastatin could decrease LVEDP, increase LVSP and±dp\/dtmax, improved thehemodynamic status.3、Compared with the operation group, atorvastatin could reduce the myocardialhypertrophy index, left ventricular non injury and mitochondrial ultrastructurepathological myocardial in Left ventricular non-infarcted zone.4、Furthermore, atorvastatin reduced the associated with ventricular remodeling inmedium of plasma BNP,serum AngII levels, serum MDA, lactate and free fatty acidaccumulation. In serum,elevated the levels of SDH,CcO,SOD,,Na＋-K＋ATPase,Ca2+-Mg2+ATPase, and the content of ATP in the non-infarced area of leftventricular were increased. moreover,down-regulated the express of proteins andmRNA of UCP2, col-I、col-III in Left ventricular non-infarcted zone.The above results between atorvastatin statins-coenzyme Q10group andatorvastatin group compared with better effect trend.5、In vitro, Compared with the hypertrophy model group,atorvastatin and atorvastatincombined with coenzyme Q10could deflate myocytes’ surface area,and then,coulddecrease the content of total protein,down-regulated the expreess of proteins ofUCP2by AngII induced.In addition, Compared with the cardiac fibroblastsproliferation group,there were obviously inhibition effects on cardiac fibroblastsproliferation,collagen secretion,and the protein expressions of col-I,col-III. Moreover,effects of atorvastatin-coenzyme Q10group were better than atorvastatin.Conclusions：1、Heart failure after myocardial infarction are involved in oxidative stress injury andventricular remodeling, atorvastatin can decrease MDA, lactate and free fatty acidcontent, improve the activity of SOD, anti-oxidation.2、there is energy metabolism disorder of heart failure after myocardial infarction,atorvastatin can improve SDH, CcO, Na+-K+ATP enzyme and Ca2+-Mg2+ATPenzyme activity, and increased the content of ATP in local tissue non-infarctedmyocardium significantly.3、Atorvastatin energy metabolism inhibition mechanism of ventricular remodelingand regulation of UCP2protein expression. The high expression of UCP2may be an important factor in myocardial fibrosis and heart failure after myocardial infarction.4、The above results has better effect in combined with coenzyme Q10group trend,suggesting coenzyme Q10have positive effect of heart failure myocardial energymetabolism of atorvastatin. The specific mechanism need further study.