Exposure Pattern Determines Methamphetamine-Induced Right Ventricular Dysfunction and Vascular Remodeling.

摘要

Methamphetamine (MA) use is a recognized risk factor for drug-associated pulmonary arterial hypertension (PAH), yet mechanisms driving methamphetamine-associated PAH (MA-PAH) remain unclear due to the lack of reproducible animal models demonstrating hemodynamic changes. This study aimed to develop a rat model of MA-PAH that reflects human patterns of MA abuse. Male Wistar rats received methamphetamine (MA, 5 mg/kg, i.p.) for 8 weeks using either a chronic daily regimen or a binge-and-crash regimen. Chronic MA administration resulted in a significant reduction in mean arterial pressure and an increase in RV systolic pressure, while ejection fraction and the Fulton index remained unchanged. In contrast, binge-crash MA exposure led to significant RV dilation, reduced RV ejection fraction, elevated RV systolic pressure, and increased RV hypertrophy. Both regimens induced pulmonary arterial medial thickening driven by smooth muscle hyperplasia; however, the binge-and-crash model exhibited more severe remodeling, including enhanced distal muscularization, sporadic endothelial proliferation, and vascular rarefaction. HMGB1 levels were significantly elevated in plasma and pulmonary microvascular endothelial cells isolated from binge-crash MA rats. In vitro, MA treatment induced HMGB1 release from endothelial cells through sigma-1 receptor signaling. Conditioned media from MA-treated endothelial cells stimulated smooth muscle cell proliferation, an effect abolished by HMGB1 neutralization. In conclusion, these findings demonstrate that binge-and-crash MA exposure produces a robust and clinically relevant PAH phenotype and identify HMGB1 as a potential mechanistic contributor linking MA exposure patterns to endothelial-smooth muscle interactions in PAH pathogenesis.