Cigarette Smoke Exacerbates Pressure Overload-Induced Right Ventricular Dysfunction via ALOX15-Mediated Ferroptosis.

Area of Science:

• Cardiovascular Biology
• Pulmonary Medicine
• Toxicology

Background:

• Chronic obstructive pulmonary disease-associated pulmonary hypertension (COPD-PH) involves right ventricular (RV) dysfunction.
• The direct role of cigarette smoke (CS) in RV failure under pressure overload is not fully understood.

Purpose of the Study:

• To investigate the direct cardiotoxic effects of CS on RV failure in a rat model of pulmonary hypertension.
• To elucidate the molecular mechanisms, particularly the ALOX15-ferroptosis pathway, involved in CS-induced RV dysfunction.

Main Methods:

• Established a rat model of pulmonary artery banding (PAB) with subsequent CS exposure.
• Assessed RV function and remodeling via echocardiography, hemodynamics, and histopathology.
• Utilized RNA sequencing and in vitro studies with RV cardiomyocytes and fibroblasts exposed to cigarette smoke extract (CSE).

Main Results:

• CS exposure exacerbated RV dysfunction, hypertrophy, fibrosis, and capillary rarefaction in PAB rats.
• Transcriptomic analysis revealed activation of the ALOX15-ferroptosis pathway in RV tissue.
• In vitro, CSE amplified Angiotensin II-induced ALOX15 upregulation and cardiac stress markers (ANP, BNP) in cardiomyocytes, which were reduced by Alox15 gene silencing or ML351 inhibition.

Conclusions:

• CS directly accelerates RV failure in pressure overload through cardiotoxic effects.
• The ALOX15-ferroptosis pathway plays a critical mechanistic role in CS-induced RV dysfunction.
• Targeting the ALOX15-ferroptosis pathway offers a potential therapeutic strategy for COPD-PH.