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

Area of Science:

• Cardiovascular Research
• Cell Biology
• Physiology

Background:

• Pulmonary arterial hypertension (PAH) is characterized by increased proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs).
• The transient receptor potential melastatin 7 (TRPM7) magnesium channel's role in PAH pathogenesis is currently unknown.
• TRPM7 is known to influence smooth muscle cell proliferation.

Purpose of the Study:

• To investigate the association between TRPM7 and PAH pathogenesis.
• To elucidate the functional role of TRPM7 in PASMCs.
• To identify the molecular mechanisms underlying TRPM7's effects in PAH.

Main Methods:

• Quantification of TRPM7 expression and currents in human and rat PASMCs under PAH conditions.
• In vitro experiments using TRPM7 inhibitors (waixenicin A) and knockdown/overexpression in PASMCs.
• In vivo studies using a rat model of hypoxia-induced PAH treated with waixenicin A.
• Analysis of the MEK/ERK signaling pathway activation in response to TRPM7 modulation.

Main Results:

• TRPM7 expression, currents, and intracellular magnesium levels were reduced in PASMCs from PAH patients, PAH rats, and in vitro PAH models.
• TRPM7 inhibition promoted PASMC proliferation and apoptosis resistance, while TRPM7 overexpression had the opposite effect.
• Pharmacological inhibition of TRPM7 exacerbated hypoxia-induced PAH features in rats.
• TRPM7 inhibition activated the MEK/ERK pathway, which mediated the pro-proliferative and anti-apoptotic effects on PASMCs.

Conclusions:

• TRPM7 acts as a negative regulator in PAH pathogenesis by suppressing PASMC proliferation and enhancing apoptosis.
• TRPM7 downregulation in PAH contributes to disease progression via MEK/ERK pathway activation.
• Restoring or enhancing TRPM7 function presents a potential therapeutic strategy for managing PAH.