title: Evidence for calreticulin attenuation of cardiac hypertrophy induced by pressure overload and soluble agonists.
abstract: While calreticulin has been shown to be critical for cardiac development, its role in cardiac pathology is unclear. Previous studies have shown the detrimental effects on the heart of sustained germline calreticulin overexpression, yet without calreticulin, the heart does not develop normally. Thus, carefully balanced calreticulin levels are required for the heart to develop and to function properly into adulthood. But what happens to calreticulin levels, and how is this regulated, during cardiac hypertrophy, during which the fetal gene program is reactivated, at least partially? Our working hypothesis was that c-Src, a kinase whose activity we previously found to be correlated with calreticulin expression, was involved with calreticulin in regulating the response to hypertrophic signals. Thus, we subjected adult mice to transverse aortic constriction to induce left ventricular hypertrophy. We found that aortic constriction caused calreticulin levels to increase, whereas those of c-Src fell with longer constriction time. We also examined the ability of embryonic stem cell-derived cardiomyocytes to respond to soluble hypertrophic agonists. Endothelin-1 treatment caused a significantly greater cell area increase of calreticulin-null cardiomyocytes, which had higher c-Src activity, compared with wild-type cells. c-Src inhibition abolished this difference. Greater c-Src activity may explain the efficacy with which calreticulin-null cells are able to induce the hypertrophic program, while cells containing calreticulin may be able to attenuate the hypertrophic response as a result of decreased c-Src activity. Thus, calreticulin may have a protective effect on the heart in the face of cardiac hypertrophy.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Medical Sciences Building, Room 6326, Toronto, Ontario, M5S 1A8 Canada.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Papp
authors.forename: Ewa
authors.initials: E
authors.lastname: Dziak
authors.forename: Golam
authors.initials: G
authors.lastname: Kabir
authors.forename: Peter
authors.initials: P
authors.lastname: Backx
authors.forename: Sophie
authors.initials: S
authors.lastname: Clement
authors.forename: Michal
authors.initials: M
authors.lastname: Opas
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D037282:Calreticulin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D003251:Constriction, Pathologic / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D011312:Pressure; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D037282:Calreticulin; D019332:Endothelin-1; D010656:Phenylephrine; D019061:src-Family Kinases