Background; Beta-Arrestins, which were originally characterized as terminators of heterotrimeric guanine nucleotide– binding protein (G protein)–coupled receptor (GPCR) signaling, also act as important signal transducers. An emerging concept in GPCR signaling is 棺-arrestin−biased agonism, in which specific ligand-activated GPCR conformational states selectively signal through 棺-arrestins, rather than through G proteins. Here, we show that mechanical stretch induced b-arrestin−biased signaling downstream of angiotensin II type I receptors (AT1Rs). Method and Results; 1.We tested whether mechanical stretch of the heart stimulates prosurvival pathways in a b-arrestin–dependent manner. Wild-type, AT1R KO, and b-arrestin KO mouse hearts were subjected to 30 min of balloon stretch to increase diastolic wall stress and induce apoptosis. Mechanical stretch of wild-type hearts led to Akt phosphorylation,which was absent in hearts from AT1R KO and b-arrestin2 KO mice. Moreover, the rate of apoptotic cell death as measured by TUNEL [terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate (dUTP) nick end labeling] staining was significantly increased in hearts from b-arrestin2 KO or AT1R KO mice compared to those from wild-type or b-arrestin1 KO mice. 2.We tested whether the angiotensin receptor blocker losartan blocks stretch-induced AT1R signaling.Stimulation of HEK 293 cells stably expressing AT1R with AngII or stretch increased phosphorylated and activated extracellular signal–regulated kinase (ERK). In contrast, pretreatment with losartan abolished both the AngII- and the stretch-mediated activation of ERK. To block AT1Rs in vivo, we pretreated mice with losartan and losartanwas added to the perfusion buffer during ex vivo stretch experiments. Administration of losartan prevents mechanical stretch–induced ERK activation in hearts. We found that mechanical stretch of wild-type hearts treated with losartan significantly increased the rate of apoptotic cell death asmeasured by TUNEL staining compared to untreated wild-type hearts. Also, in hearts subjected to mechanical stretch, losartan treatment increased DNA fragmentation, caspase 3/7 activity, and the ratio of Bax to Bcl2 protein compared to untreated stretched hearts. Conclusion; These data show that the heart responds to short-term increases in mechanical stress by activating 棺-arrestin , AT1R mediated cell survival signals and the angiotensin receptor blocker losartan blocks stretch-induced AT1R signaling.