Regulated expression of GRP78 during vasopressin induced hypertrophy of heart-derived myocytes

Although the development of cellular hypertrophy is widely believed to involve Ca2+ signaling, potential supporting roles for sequestered Ca2+ in this process have not been explored. H9c2 cardiomyocytes, respond to arginine vasopressin with an initial mobilization of Ca2+ stores and reduced rates of mRNA translation followed by repletion of Ca2+ stores, up-regulation of translation beyond initial rates, and the development of hypertrophy. Rates of synthesis of the endoplasmic reticulurn (ER) chaperones, GRP78 and GRP94, were found to increase preferentially at early times of vasopressin treatment. Total GRP78 content increased 2- to 3-fold within 8 h after which the chaperone was subject to post-translational modification. Preferential synthesis of GRP78 and the increase in chaperone content both occurred at pM vasopressin concentrations and were abolished at supraphysiologic Ca2+ concentrations. Co-treatment with phorbol myristate acetate decreased vasopressin-dependent Ca2+ mobilization and slowed appearance of new CRP78 molecules in response to the hormone, whereas 24 h pretreatment with phorbol ester prolonged vasopressin-dependent Ca2+ mobilization and further increased rates of GRP78 synthesis in response to the hormone. Findings did not support a role for newly synthesized GRP78 in translational up-regulation by vasopressin. However up-regulation, which does not depend on Ca2+ sequestration, appeared to expedite chaperone expression. This report provides the first evidence that a Ca2+-rnobilizing hormone at physiologic concentrations signals increased expression of GRP78. Translational tolerance to depletion of ER Ca2+ stores, typifying a robust ER stress response, did not accompany vasopressin-induced hypertrophy. (C) 2001 Wiley-Liss, Inc.