Action Mechanisms Of Salusins As A Group Of Novel Cardiomyocyte Survival Factors

Salusin-α and Salusin- β are newly discovered TOR-related peptides consisting of 28 and 20 amino acids and designated salusin-a and salusin-β, respectively. Studies have suggested that salusins may be a novel class of regulatory peptides affecting the cardiovascular system in an endocrine and/or paracrine manner, and may have physiological and pathological significance in regulation of cardiovascular activity and diseases. However, the cardiovascular effects of salusins are not well known. In the present study, we observed the effects of salusins on serum deprivation and H₂O₂-induced apoptostic injury in cultured neonatal rat cardiomyocytes in vitro. The findings showed that salusins protected cadiomyocytes against serum deprivation and H₂O₂-induced apoptostic injury, and increased protein expressive level of GRP78 and bcl-2, and suppressed caspase-3 activity, and decreased the calcium transient frequency. The cytoprotective effect of salusin-β on cardiomycytes was abrogated with phosphatidylinositol 3-kinase (PI3-kinase) inhibitor LY-294002, as well as both the effect of salusins on GRP78 expression and caspase-3 activity. An antisense oligodeoxynucleotide (ODN) targeted against the grp78 gene was designed to reduce GRP78 expression in a sequence-specific and to attenuate the cytoprotective effect of salusin-β on cardiomyocytes against serum deprivation-induced apoptostic injury. Overexpression of GRP78 was obtained by gene transfer via recombinant adenoviral vector encoding GRP78 cDNA, which prevented serum deprivation-induced cardiomyocytes apoptosis effectively. These foundings suggested that salusins may be novel cardiomyocytes survival factors, exerting the role by up-regulating GRP78 expression and inhibiting capases-3 activity via a PI3 kinase pathway.