L-tetrahydropalmatine attenuates methamphetamine-induced pulmonary vascular remodeling via CaSR-BMP2/mTOR signaling

The World Symposium on Pulmonary Hypertension (WSPH) raised a new classification, "Drug- and toxin-induced pulmonary arterial hypertension (PAH)", in which methamphetamine (MA) is recognized as an important contributor. L-tetrahydropalmatine (L-THP), an alkaloid with analgesic and sedative properties, has demonstrated vascular protective effects, but its mechanism against MA-induced pulmonary injury remains unclear. The calcium-sensing receptor (CaSR) regulates multiple cellular processes, including proliferation, differentiation, migration, adhesion, and Apoptosis, and may participate in MA-related pulmonary vascular remodeling. This study investigated whether MA can induce Autophagy and pulmonary artery smooth muscle cells (PASMCs) proliferation, and whether L-THP can attenuate MA-induced pulmonary arterial remodeling via CaSR-related mechanisms. Rats were randomly assigned to control, MA and L-THP + MA groups. Chronic MA exposure altered pulmonary hemodynamics, increased Autophagy, and promoted pulmonary vascular remodeling. It was confirmed that Bone Morphogenetic Protein 2 (BMP2) interacted with mammalian target of rapamycin (mTOR). L-THP reversed MA-induced hemodynamic changes, downregulated the level of CaSR, and inhibited MA-induced Autophagy through BMP2/mTOR interaction to reduce the proliferation of PASMCs and prevent pulmonary vascular remodeling. This study is the first to demonstrate that L-THP suppresses MA-induced Autophagy in PASMCs through modulation of CaSR, providing experimental evidence supporting L-THP as a potential protective strategy for MA-associated PAH.

Autophagy; BMP2; CaSR; L-tetrahydropalmatine; Methamphetamine; Pulmonary hypertension; Remodeling; mTOR.