The Role And Mechanism Of ALDH2 In Early Compensatory Cardiac Hypertrophy

Cardiac hypertrophy is the response to long-time pressure or volume overload, which can be sort to early compensatory and late decompensated cardiac hypertrophy. In the situation of pressure overload,the myocyte goes through hypertrophy to overcome the increased afterload and maintain normal cardiac function. A lot of factors participate in the process of heart failure, which contain gene expression, hormone, apoptosis, energy metabolic disorders, Oxidative stress, arrhythmia, vascular dysfunction, collagen deposition and so on. Heart failure will occurr early if the compensatory process is damaged.Aldehyde dehydrogenase 2(ALDH2) exists in the mitochondria which takes part in the redox reaction. It has been found to play an important part in the cardiovascular disease. To expolre the role of ALDH2 in caidiac hypertrophy, firstly we carried out transverse aorta constriction (TAC) to establish cardiac hypertrophy in the ALDH2 knockout mice(ALDH2-/-) and wild type mice(WT). The result turned out that the cross area of myocyte(CSA),heart body weight ratio(HW/BW), the wall thickness of ALDH2-/-mice are lower than that WT mice. In the mean time, cardiac function of ALDH2-/-mice was worse than WT mice, which meansed that ALDH2 played an important part in the compentory cardiac hypertrophy. To explore the mechanism, we cultured myocyte and then stretched, and It was found that ALDH2 protein decreased when the cells underwent stretched. To discover the mechanism, we cultured myocyte and stretched after small RNA inference for ALDH2.It was found that, the phosphorylation level of ERK, P38, AKT in the inference group was lower than control group, which meaned that ALDH2 may played it's role by affecting activation of these signaling molecules. ATP is the substrate for the process of phosphorylation and it also supplys energy for the body. If the supply of ATP is damaged, it will disturb the energy metabolism and the function. To explore if ALDH2 could affect energy, we observed the difference between control and inference group.The total ATP level in inference group was less than control group.which meaned ALDH2 could affect energy metabolism.In conclusion, ALDH2 plays an important part in the early compensated cardiac hypertrophy induced by pressure overload. ALDH2 could affect the activation of the molecules which participate in the compensated hypertrophy and myocyte energy metabolism to accomplish it's role.Part 1ALDH2 participates in the early cardiac compensated hypertrophy induced by pressure overloadPurpose To observe if ALDH2 paiticipates in the early cardiac compensated hypertrophy induced by pressure overload. Method Wild type (WT) and knock out (KO) mice underwent transverse aortic constriction (TAC)and sham operation (SHAM) respectively. Cardiac structure and function of each group were measured by B ultrasonic examination in the time of one week and two weeks after operation. Cross section area of myocyte (CSA) were measured after HE stain. Results Comparing with wild type transverse aorta constriction(WT-TAC) group, cardiac ejection fraction decreased early after transverse aorta constriction in ALDH2 knockout group(p<0.05), the value are 85.08% and 78.19% respectively. Left ventricle diastolic and systolic posterior wall thickness (PWSth; PWDth), heart weight-to-body weight ratio (HW/BW) myocyte cross section area(CSA) are lower in knockout transverse aorta constriction group (KO-TAC) than wild type miceConclusion Early stage compensatory cardiac hypertrophy after pressure-overload is injured in ALDH2 knockout mice and the cardiac function decreased earlier which means ALDH2 plays an important protective role in the process of compensatory cardiac hypertrophy. Part 2ALDH2 could affect the activation of MAPKS and AKT induced by stretchingPurpose To explore the role of ALDH2 in the activation of MAPKs and AKT in the stretched myocyte.Method we cultured myocyte of neonate rats and then stretched them afte performing ALDH2 small RNA inference. West blot was performed to detected the phosphorylation of the molecules which participated in the signal transduction of cardiac hypertrophy between control group and inference group.Result Comparing with control group, the phosphorylationof ERK, P38, AKT was lower in the inference group after stretching. Conclusion ALDH2 could play its part in the cardiac hypertrophy by affecting the activation of signal molecules.Part 3 ALDH2 could affect myocyte energy metabolismPurpose To observe if ALDH2 could affect energy metabolism of myocyte. Method Neonate rat myocyte was cultured and then performed ALDH2 small RNA inference. ATP was detected using luciferase. Result Comparing with control group, the level of ATP of inference group was lower.Conclusion ALDH2 played an important part in the energy metabolism of myocyte.Conclusion1. ALDH2 played an activate part in the early compensated cardiac hypertrophy. 2. ALDH2 could affect the phosphorylation of the molecules which participated in the compensated cardiac hypertrophy.3. ALDH2 could affect myocyte energy metabolism.Potential application and noveltyWe proved that ALDH2 could affect both the phosphorylation of the signal molecules which take part in the early compensated cardiac hypertrophy and the energy metabolism of myocyte to accomplish it role in cardiac hyperteophy induced by pressure overload.