Abstract Body: Adipose derived stem cells (ADSCs) are attracting wide spread interest for treating and preventing cardiovascular diseases. Various strategies such as preconditioning approaches effectively enhance the survival, homing and protective effects of stem cells. In this study, the effect of different duration of hypoxia preconditioning on AngII induced cell death was determined by cell viability assay. Further, 6 h of hypoxia was determined as the brief preconditioning period for ADSCs which resulted in the elevation of factors associated with angiogenesis, survival and stem cell homing in ADSCs. The efficiency of hypoxia-preconditioned-ADSCs (hypADSCs) over ADSCs on cardio-protection was determined by administering them in hypertensive SHR rats. Changes in cardiac characteristics were determined by echocardiography, histological staining and western blotting. In SHRs, hypADSC effectively restored the cardiac function as determined by cardiac contractility and showed significant reduction in hypertension associated cardiac apoptosis. Further analysis showed that the hypADSC restored the AMPK signaling in the SHR hearts and elevated their cell survival mechanism and thereby prevents cardiomyocyte lose in hypertension condition. The hypADSC administration in SHRs showed better cardio-protection than ADSCs by regulating the cardiac function and reducing cardiac apoptosis and therefore brief hypoxia is a critical factor for beneficial stem cell vigor.