Abstract 822: Enhanced Left Ventricle TGFβ2 Signaling in a Model of Dilated Cardiomyopathy

Pathological gene transcription and induction of proinflammatory signaling is a hallmark of dilated cardiomyopathy (DCM) and HF. Previous studies from our lab identified TGFβ2 as a putative driver of inflammation during DCM progression. To study the role of TFGβ2 in DCM hearts, we analyzed TFGβ signaling networks, as well as TFGβ2-induced gene expression changes from mice carrying a human DCM mutation in phospholamban (PLN R9C ). ELISA was used to confirm TGFβ isoform levels in PLN and wild type (WT) hearts: only TGFβ2 was significantly increased in PLN R9C mice (TGFβ1: 1.6-fold, p=0.15; TGFβ2: 9.6-fold, p=0.01; TGFβ3: 1.0-fold, p=0.88) (Figure). Levels of total SMAD2 (1.5-fold, p=0.002), phosphorylated SMAD2 (P-SMAD2; 3.9-fold, p=0.0003), and the P-SMAD2/SMAD2 ratio (2.6-fold, p=0.0004) were greater in PLN R9C mice. Treatment with exogenous TGFβ2 results in activation of cultured cardiac fibroblasts from WT hearts ( Col1a1 (3.3-fold), Col4a1 (2.7-fold), Ctgf (6.4-fold), Eng (2.6-fold), Fn1 (2.8-fold), Lox (2.6-fold), Mmp2 (2.8-fold), Postn (4.1-fold), Rhob (3.6-fold), Tgfb1 (3.6-fold), Tgfb2 (2.9-fold), Tgfb3 (3.0-fold), Tie1 (2.4-fold), Thsb1 (4.3-fold)). Our results demonstrate that TGFβ2 levels are increased and that TGFβ signaling is activated in PLN R9C hearts with DCM. These data suggest that TGFβ2 is a specific and potent inflammatory mediator in the heart and mark this isoform as a potential therapeutic target in DCM.