TRPM7 channel inhibition exacerbates pulmonary arterial hypertension through MEK/ERK pathway

The increased proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) drive the progression of pulmonary arterial hypertension (PAH). The transient receptor potential melastatin 7 (TRPM7) is an endogenous magnesium channel reported to promote the proliferation of SMCs. However, whether TRPM7 is associated with PAH pathogenesis remains uncharacterized. We found that TRPM7 was downregulated in PASMCs from PAH human and Sprague-Dawley rats with hypoxia-induced PAH. Similar results were reproduced in PASMCs treated with PAH stimuli in vitro. Additionally, the TRPM7 currents and intracellular magnesium level in PASMCs were also reduced by PAH stimuli. Functionally, TRPM7 inhibition with waixenicin A or knockdown promoted, and reversely, its overexpression inhibited the proliferation and apoptosis resistance of PASMCs. Moreover, waixenicin A exacerbated hypoxia-induced PAH features in rats. Furthermore, TRPM7 inhibition activated MEK/ERK pathway, and the effects of TRPM7 inhibition were drastically attenuated by pathway specific inhibitor U0126, thus suggesting that activating MEK/ERK pathway is a predominant mechanism through which TRPM7 inhibition exacerbates PAH. In summary, these results may identify TRPM7 as a novel negative regulator in PAH pathogenesis, and suggest that improving its function may represent an antagonistic strategy to modify PAH progression.