Blocking Sigmar1 exacerbates methamphetamine-induced hypertension

Area of Science:

• Cardiovascular Pharmacology
• Vascular Biology
• Drug-Induced Conditions

Background:

• Chronic methamphetamine (METH) exposure is a significant risk factor for developing hypertension.
• The precise mechanisms driving METH-induced hypertension and associated vascular changes are not fully understood.

Purpose of the Study:

• To elucidate the underlying mechanisms of METH-induced hypertension.
• To investigate the role of the Sigma1 receptor (Sigmar1) in METH-induced vascular remodeling and hypertension.

Main Methods:

• A mouse model of METH-induced hypertension was established.
• Vascular remodeling, blood pressure (BP), and Sigmar1 expression were assessed in METH-exposed wild-type (WT) and Sigmar1 knockout (KO) mice.
• Mice were pretreated with a Sigmar1 antagonist (BD1047) or agonist (PRE-084) before METH exposure.
• The differentiation of vascular smooth muscle cells (VSMCs) and mesenchymal stem cells, collagen secretion, and the TGF-β/Smad2/3 signaling pathway were analyzed.

Main Results:

• METH exposure led to increased BP, vascular remodeling with collagen deposition, and elevated Sigmar1 levels in WT mice.
• Sigmar1 KO mice and antagonist-treated mice exhibited exacerbated hypertension and vascular fibrosis following METH exposure.
• Agonist treatment prevented METH-induced increases in BP and collagen.
• METH induced VSMC and stem cell differentiation into myofibroblast-like cells, increasing collagen secretion.
• Sigmar1 was found to suppress COL1A1 expression by inhibiting the TGF-β/Smad2/3 pathway in METH-exposed cells.

Conclusions:

• Sigmar1 plays a critical role in METH-induced hypertension and vascular fibrosis.
• Sigmar1 mitigates METH-induced vascular damage by inhibiting the TGF-β/Smad2/3 signaling pathway.
• Targeting Sigmar1 presents a potential therapeutic strategy for managing METH-induced hypertension and associated vascular fibrosis.