β 3 -adrenergic receptor activation induces TGFβ1 expression in cardiomyocytes via the PKG/JNK/c-Jun pathway.

In heart failure, the expression of cardiac β ₃ -adrenergic receptors (β ₃ -ARs) increases. However, the precise role of β ₃ -AR signaling within cardiomyocytes remains unclear. Transforming growth factor β1 (TGFβ1) is a crucial cytokine mediating the cardiac remodeling that plays a causal role in the progression of heart failure. Here, we set out to determine the effect of β ₃ -AR activation on TGFβ1 expression in rat cardiomyocytes and examine the underlying mechanism. The selective β ₃ -AR agonist BRL37344 induced an increase in TGFβ1 expression and the phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun in β ₃ -AR-overexpressing cardiomyocytes. Those effects of BRL37344 were suppressed by a β ₃ -AR antagonist. Moreover, the inhibition of JNK and c-Jun activity by a JNK inhibitor and c-Jun siRNA blocked the increase in TGFβ1 expression upon β ₃ -AR activation. A protein kinase G (PKG) inhibitor also attenuated β ₃ -AR-agonist-induced TGFβ1 expression and the phosphorylation of JNK and c-Jun. In conclusion, the β ₃ -AR activation in cardiomyocytes increases the expression of TGFβ1 via the PKG/JNK/c-Jun pathway. These results help us further understand the role of β ₃ -AR signaling in heart failure.
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