Loss of LRRC25 accelerates pathological cardiac hypertrophy through promoting fibrosis and inflammation regulated by TGF-β1

Despite advances in therapeutic strategies, heart failure-associated mortality rates remain high. Thus, understanding the pathophysiological molecular mechanisms involved in the remodeling process is essential for developing new and effective therapies. LRRs are present various prokaryotic and eukaryotic proteins and important for the innate immune system via regulating protein-protein interactions. LRRC25 is a member of leucine-rich repeat (LRR)-containing protein family. LRRC25 has been shown to negatively modulate nuclear factor κB (NF-κB) activation, a crucial factor related to cardiac hypertrophy. Our aim was to explore the effects of LRRC25 on cardiac hypertrophy. In the present study, LRRC25 levels were decreased in human and mouse hypertrophied hearts. LRRC25 knockout exacerbated cardiac hypertrophy responding to pressure overloading or angiotensin II (Ang II) stimulation. Deletion of LRRC25 accelerated cardiac dysfunction and fibrosis in mice subjected to aortic banding (AB). LRRC25 ablation induced a strong increase in the transcription of both hypertrophy (ANP, BNP, and β-MHC) and fibrosis associated molecules (col1, col3a1, α-SMA and fibronectin). In addition, the expression of transforming growth factor-β1 (TGF-β1), and its down-streaming signals of phosphorylated Smad2/3, was markedly induced by LRRC25 deficiency. LRRC25-knockout mice showed a significantly enhanced inflammation in response to AB surgery by promoting the activation of NF-κB signaling pathway. In mouse cardiomyocytes, LRRC25 deficiency markedly elevated TGF-β1 and NF-κB activation stimulated by Ang II. Treatment with a combination of TGF-β1 or NF-κB inhibitor abolished the effects of LRRC25-knockout on the promotion of cardiac hypertrophy in vitro. Together, our study identified LRRC25 as a critical molecular switch whose down-regulation resulted in cardiac hypertrophy in a TGF-β1- and NF-κB-dependent manner.