Adapter molecule DOC-2 is differentially expressed in pressure and volume overload hypertrophy and inhibits collagen synthesis in cardiac fibroblasts

Abstract

DOC-2 (differentially expressed in ovarian carcinoma) is involved in Ras-, beta-integrin-, PKC-, and transforming growth factor-beta-mediated cell signaling. These pathways are implicated in the accumulation of extracellular matrix proteins during progression of hypertrophy to heart failure; however, the 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 and 2) examine its role in growth factor-mediated ERK activation and collagen production. Pressure overload and volume overload were induced for 10 wk in Sprague-Dawley rats by aortic constriction and by aortocaval shunt, respectively. ANG II (0.3 mg.kg(-1).day(-1)) was infused for 2 wk. Results showed that, compared with myocytes, DOC-2 was found abundantly expressed in cardiac fibroblasts. Treatment of cardiac fibroblasts with ANG II and TPA resulted in increased expression of DOC-2. Overexpression 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 pressure overload and after ANG II infusion, increased collagen mRNA correlated with reduced DOC-2 levels, whereas in volume overload 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.

Signal pathways involved in reverse remodeling of the hypertrophic rat heart after pressure unloading

“…Hypertrophic remodeling in the present experiment, as assessed by heart weight, left ventricular weight, cardiomyocyte area and collagen deposition was similar to that previously described in the study of hypertrophic hearts [20]. Our data suggested that hypertrophy induced by AAC was associated with no myofibrillar alignment and slightly decreased ejection fraction, indicating no cardiac dysfunction; therefore, the model best represents a state of "compensated" pressure overload-induced hypertrophy.…”

Ferroptosis Related Genes in Ischemic and Idiopathic Cardiomyopathy: Screening for Potential Pharmacological Targets

“…Cardiac fibroblast activation promotes the accumulation of collagen types I and III, which are major fibrin of the myocardial collagen matrix. The structural remodeling of cardiac interstitium is a major determinant of pathological hypertrophy ( Kumbar et al, 1985 ). Targeted inhibition of ferroptosis may be a new direction for the treatment of ischemic/idiopathic cardiomyopathy.…”

Targeted disruption of Hspa4 gene leads to cardiac hypertrophy and fibrosis

“…Connective tissue growth factor (CTGF) plays an important role in the development of fibrosis in different tissues, including the heart [33]. Adapter molecule DAB2 (DOC-2) inhibits collagen synthesis in cardiac fibroblasts [34]. In the microarray analysis, Ctgf mRNA was found to be up-regulated in the Hspa4 KO hearts (Suppl.…”