Human RPS6 peptide

Mammalian target of rapamycin (mTOR), a serine/threonine kinase plays an important role in various pathophysiological processes including cancer, metabolic diseases, and inflammation. Although mTOR participates in Toll-like receptor 4 signalling in different cell types, the role of this enzyme in sepsis pathogenesis and its effects on hypotension and inflammation in endotoxemic rats remains unclear. In this study we investigated the effects of mTOR inhibition on lipopolysaccharide (LPS)-induced changes on expressions and/or activities of ribosomal protein S6 (rpS6), an mTOR substrate, nuclear factor-kappa B (NF-kappa B) p65, inhibitor kappa B (I kappa B)-alpha, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 with production of nitric oxide, peroxynitrite, prostacyclin, and tumor necrosis factor (TNF)-alpha and activity of myeloperoxidase (MPO), which results in hypotension and inflammation. Injection of LPS (10 mg/kg, i.p.) to male Wistar rats decreased blood pressure and increased heart rate that were associated with elevated nitrotyrosine, 6-keto-PGF(1a), and TNF-alpha levels and MPO activity, and increased expressions and/or activities of rpS6, NF-kappa B p65, iNOS, and COX -2 and decreased expression of I kappa B-alpha in renal, cardiac, and vascular tissues. LPS also increased serum and tissue nitrite levels. Rapamycin (1 mg/kg, i.p.) given one h after injection of LPS reversed these effects of LPS. These data suggest that the activation of mTOR/I kappa B-alpha/NF-kappa B pathway associated with vasodilator and proinflammatory mediator formation contributes to LPS-induced hypotension and inflammation.

Cardiac adaptation to unremitting physiological stress typically involves hypertrophic growth of cardiomyocytes, a compensatory response that often fails and causes heart disease. Gene array analysis identified AKIP1 (A Kinase Interacting Protein 1) as a hypertrophic gene and we therefore hypothesized a potential role in the hypertrophic response. We show for the first time that both AKIP1 mRNA and protein levels increased in hypertrophic cardiomyocytes under conditions of sustained cardiac stress, including pressure overload and after myocardial infarction and in vitro in phenylephrine (PE) stimulated neonatal rat ventricular cardiomyocytes (NRVCs). AKIP1 overexpression in NRVCs markedly stimulated hypertrophic growth responses, including significantly increased cell size, augmented cytoskeletal organization and protein synthesis. Although, AKIP1 was not essential for PE induced hypertrophy in NRVCs, it did potentiate neurohormonal induced protein synthesis. AKIP1 did, however, not induce expression of pathological marker genes like ANP and -MHC. ERK and Akt kinase signaling pathways have been linked to hypertrophy and AKIP1 specifically induced phosphorylation of Akt. This phosphorylation of Akt was essential for activation of ribosomal rpS6 and translation elongation factor eEF2 and this readily explains the increased protein synthesis. Akt inhibition fully blocked AKIP1 induced hypertrophy, showing that this pathway is critically involved. In conclusion, our results show that AKIP1 is induced in hypertrophic hearts and can stimulate adaptive cardiomyocyte growth, which involves Akt signaling.