IMM-H007 attenuates isoprenaline-induced cardiac fibrosis through targeting TGFβ1 signaling pathway

Abstract

Upon chronic stress, β-adrenergic receptor activation induces cardiac fibrosis and leads to heart failure. The small molecule compound IMM-H007 has demonstrated protective effects in cardiovascular diseases via activation of AMP-activated protein kinase (AMPK). This study aimed to investigate IMM-H007 effects on cardiac fibrosis induced by β-adrenergic receptor activation. Because adenosine analogs also exert AMPK-independent effects, we assessed AMPK-dependent and -independent IMM-H007 effects in murine models of cardiac fibrosis. Continual subcutaneous injection of isoprenaline for 7 days caused cardiac fibrosis and cardiac dysfunction in mice in vivo. IMM-H007 attenuated isoprenaline-induced cardiac fibrosis, diastolic dysfunction, α-smooth muscle actin expression, and collagen I deposition in both wild-type and AMPKα2^-/- mice. Moreover, IMM-H007 inhibited transforming growth factor β1 (TGFβ1) expression in wild-type, but not AMPKα2^-/- mice. By contrast, IMM-H007 inhibited Smad2/3 signaling downstream of TGFβ1 in both wild-type and AMPKα2^-/- mice. Surface plasmon resonance and molecular docking experiments showed that IMM-H007 directly interacts with TGFβ1, inhibits its binding to TGFβ type II receptors, and downregulates the Smad2/3 signaling pathway downstream of TGFβ1. These findings suggest that IMM-H007 inhibits isoprenaline-induced cardiac fibrosis via both AMPKα2-dependent and -independent mechanisms. IMM-H007 may be useful as a novel TGFβ1 antagonist.

Keywords: AMP-activated protein kinase; IMM-H007; cardiac fibrosis; sympathetic stress; transforming growth factor β1.