Experimental Study On Transplantation Of Human Umbilical Cord Blood Mesenchymal Stem Cells Combined With Enalapril And The Related Mechanisms In The Treatment Of Acute Myocardial Infarction

Chapter1:Impacts of Enalapril on apoptosis of human umbilical cord blood mesenchymal stem cells under oxidative stress in vitroBackgroundInflammation and oxidative stress play an important role in homing and survive of transplanted umbilical cord blood mesenchymal stem cells. Enalapril has been proved that can inhibit oxidative stress after acute myocardial infarction. We hypothesize that Enalapril might improve viability of hUCMSCs and inhibit apoptosis of stem cells via inhibition of oxidative stress after acute myocardial infarction.Methods and resultsWe simulated oxidative stress micro-environment via H2O2in vitro. Enalapril or LY29402were added into normal hUCMSCs solution or oxidative stress solution. Viability and migration of hUCMSCs were respectively assessed by MTT and Transwell methods. Apoptosis of hUCMSCs were assessed by Annexin-V-FITC/PI method. The results showed that Enalapril could improve survival and migration of hUCMSCs, reduce apoptosis of hUCMSCs under oxidative stress environment. LY294002, an inhibitor of PI3K, promoted apoptosis and inhibited survival of hUCMSCs. Expression of apoptotic protein pAKt, pGSK-3βser9,caspase3were tested by western-blot methods. In the environment of oxidative stress, Enalapril intervention group demonstrated a significantly increase in the level of pAKt, pGSK-3βser9and a market decrease in the level of caspase3.ConclusionsEnalapril could promote survival and migration of hUCMSCs and reduce apoptosis of hUCMSCs in the environment of oxidative stress in vitro. The mechanism may be involved with increase of pAKt, pGSK--3β and decrease of caspase3. Chapter2Impacts of Enalapril on the survival of human umbilical cord blood mesenchymal stem cells and cardiomyocytes apoptosis in the infracted heart via intervention of myocardial micro-environmentBackgroundCell transplantation of human umbilical cord blood mesenchymal stem cells is a new treatment that has effective but limited impacts on acute myocardial infarction. Enalapril is a common clinical medicine of angiotensin converting enzyme inhibitors (ACEI) for acute myocardial infarction that could improve ventricular remodeling. We hypothesize that Enalapril might increase survival of transplanted cells in infracted heart, and improve outcome of ventricular remodeling after myocardial infarction via inhibition of cardiomyocytes apoptosis.Methods and resultsHuman umbilical cord blood mesenchymal stem cells were injected intravenously to the rabbits underwent myocardial infarction with previously intragastric administration of enalapril. There were two other groups that received either stem cells transplantation or Enalapril alone. The survival of implanted cells was determined by green fluorescent protein(GFP) labeling. The results demonstrated that the amount of grafted cells survived in the infracted area was significantly increased in the rabbits received combination of Enalapril and transplantation of stem cells. More viable cardiomyocytes and less expression of collagen protein were observed in combination treatment rabbits than other treatments ones. Apoptosis of cardiomyocytes were assessed by TUNNEL. Combination treatment rabbits showed significant benefits in inhibiting apoptosis of cardiomyocytes compared to ones treated with either stem cells transplantation or Enalapril alone.Conclusions Combination of Enalapril and transplantation of hUCMSCs markedly increased the amount of grated cells survived in the infracted heart, beneficially influenced ventricular remodeling and inhibited cardiomyocytes apoptosis. Chapter3Enalapril enhances therapeutic efficacy on acute myocardial infarction with transplantation of human umbilical cord blood mesenchymal stem cells via intervention of myocardial micro-environmentBackgroundInflammation, oxidative stress, hypoxia are the main characters in the myocardial micro-environment after AMI. Inflammation and oxidative stress play an important role in cardiac remodeling post-MI. We hypothesize that Enalapril might enhances therapeutic efficacy on AMI with transplantation of hUCMSCs via inhibition of inflammation and oxidative stress in the myocardial micro-environment after AMI.Methods and resultsHuman umbilical cord blood mesenchymal stem cells were injected intravenously to the rabbits underwent myocardial infarction with previously intragastric administration of Enalapril. There were two other groups that received either stem cells transplantation or Enalapril alone. Cardiac functions were assessed by echocardiography. Expression of inflammatory factor TNF-awere assessed by Immunohistochemical methods and real time PCR. Oxidative stress was reflected by content of MDA and SOD activity. The results indicated that combination of Enalapril and transplantation of hUCMSCs showed significantly benefits in preservation of cardiac functions. Compared with stem cells transplantation or Enalapril alone, the combination treatment also showed a significant decrease in the level of the pro-inflammatory TNF-a, content of MDA and ACE activity, and a market increase in SOD activity in the infracted myocardium.ConclusionsCombination of Enalapril and transplantation of hUCMSCs markedly increased cardiac function, beneficially influenced inflammation and oxidative stress after acute myocardial infarction. It maybe related with inhibiting ACE activity in the infracted myocardium via Enalapril.