Journal of Applied Physiology
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J Appl Physiol (January 25, 2007). doi:10.1152/japplphysiol.00924.2006
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Submitted on August 21, 2006
Accepted on January 18, 2007

Adapter Molecule DOC-2 is differentially expressed in Pressure and Volume Overload Hypertrophy and Inhibits Collagen Synthesis in Cardiac Fibroblasts

Deepa H Kumbar1, Andrew VanBergen1, Catherina Ocampo1, Sunthorn Muangmingsuk1, Andrew J Griffin2, and Madhu Gupta2*

1 Pediatrics, The Heart Institute for Children, Hope Childrens Hospital, Oak Lawn, Illinois, United States
2 Pediatrics, The Heart Institute for Children, Hope Childrens Hospital, Oak Lawn, Illinois, United States; Pediatrics, Rush University Medical Center, Chicago, Illinois, United States

* To whom correspondence should be addressed. E-mail: molb99{at}uic.edu.

DOC-2 is involved in Ras, {beta}-integrin, PKC and TGF{beta} mediated cell signaling. These pathways are implicated in the accumulation of ECM proteins during progression of hypertrophy to heart failure; however, role of DOC-2 in cardiac pathophysiology has never been examined. This study was undertaken to (1) analyze DOC-2 expression in primary cultures of cardiac fibroblasts and cardiac myocytes and in the heart following different types of hemodynamic overloads (2) examine its role in growth factor mediated ERK activation and collagen production. Pressure(PO)-and-volume(VO)-overloads were induced for 10 weeks in adult male Sprague Dawley rats by aortic constriction and by aorto-caval shunt, respectively. Angiotensin II (AII, 0.3mg/kg/day) was infused for 2 wks. Results showed that as compared to myocytes, DOC-2 was found abundantly expressed in cardiac fibroblasts. Treatment of cardiac fibroblasts with AII and TPA resulted in increased expression of DOC-2. Over-expression of DOC-2 in cardiac fibroblasts led to inhibition of hypertrophy agonist stimulated ERK activation and collagen expression. An inverse correlation between collagen and DOC-2 was observed in in vivo models of cardiac hypertrophy; in PO and following AII infusion, increased collagen mRNA correlated with reduced DOC-2 levels, whereas in VO, increased DOC-2 levels were accompanied by unchanged collagen mRNA. These data for the first time describe expression of DOC-2 in the heart and demonstrate its modulation by growth-promoting agents in cultured cardiac fibroblasts and in in vivo models of heart hypertrophy. Results suggest a role of DOC-2 in cardiac remodeling involving collagen expression during chronic hemodynamic overload.






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