What does this research mean for the field?

Cigarette smoke drives pulmonary vascular remodeling by inducing isolevuglandin formation in smooth muscle cells, which inhibits mitochondrial Sirtuin-3 and promotes persistent HIF-1α signaling. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to investigate the role of cigarette smoke in smooth muscle cell activation and its contribution to pulmonary vascular remodeling.

May 20, 2026

D109-10 Cigarette Smoke Directly Activates Smooth Muscle Cells to Cause Pulmonary Vascular Remodeling

Key Points

This research aims to investigate the role of cigarette smoke in smooth muscle cell activation and its contribution to pulmonary vascular remodeling.
Mice were exposed to chronic cigarette smoke twice daily for 2 months.
Histological evaluation and western blot techniques were used to assess lung tissue and marker expressions.
Mice models included wild type, SMC-specific Sirt3 overexpressing, and SMC-specific HIF-1α knockout.
Cigarette smoke exposure resulted in increased thickness of intrapulmonary vessel walls and mild emphysema in wild type mice.
Isolevuglandin formation and stabilization of HIF-1α were significantly increased in lung lysates post-cigarette smoke exposure.
Both SMC-HIF1a-/- and SMC-Sirt3OX mice exhibited reduced vascular remodeling and emphysema in response to cigarette smoke.

Abstract

Abstract Rationale Pulmonary vascular (PV) remodeling can occur in mild COPD and smokers with normal lung function. Prior studies indicate that effector cells for cigarette smoke (CS)-induced PV remodeling originate from smooth muscle cells (SMCs). We hypothesized that CS inhibits the mitochondrial deacetylase Sirtuin-3 (Sirt3) in SMCs and Sirt3 inhibition in SMCs increases hypoxia-inducible factor 1-alpha (HIF-1α) activation, thereby driving PV remodeling. Methods Wild type (WT), SMC-specific Sirt3 overexpressing (SMC-Sirt3OX), and SMC-specific HIF-1α knockout (SMC-HIF1a-/-) mice (C57BL/6J background) were exposed to chronic CS (two times per day with 12 cigarettes each treatment) using a SIU24 CS machine (Promech, Vintrie, Sweden). Lungs were collected for histological evaluation and isolevuglandin formation, Sirt3 expression, superoxide dismutase 2 (SOD2) acetylation, and HIF-1α expression measurements by western blot. Formalin-fixed paraffin-embedded lung sections were stained with Elastica-van Gieson. No differences were observed between control groups for all measurement performed; therefore, these mice were combined for comparisons with CS exposed groups. Results We identified abnormal muscularization of intrapulmonary vessels and PV remodeling with increased t.intima and t.media thickness after 2 months of CS exposure in WT mice, along with mild emphysema (MLI 25.5±1.7µm in CS exposed mice compared to 22.1±1.0µm in unexposed mice). In addition, CS exposure increased isolevuglandin formation, SOD2 acetylation, and HIF-1α stabilization in lung lysates. While isolevuglandin-containing proteins were minimally detected in control lungs, robust immunostaining for isolevuglandin-adducted proteins was detected following 2 months of CS exposure, particularly in SMCs and endothelial cells. Both SMC-HIF1a-/- and SMC-Sirt3OX, mice showed reduced t.media and t.intima thickening in response to CS and emphysema was also reduced in SMC-HIF1a-/- mice. Conclusions CS induces formation of isolevuglandins in SMCs, which inhibit mitochondrial Sirtuin-3 and SOD2, resulting in oxidative stress and persistent HIF-1α signaling, thereby driving PV remodeling. This abstract is funded by: Supported by the 5I01BX002378 from the Department of Veterans Affairs and 23CDA1042910 https://doi.org/10.58275/AHA.23CDA1042910.pc.gr.168009 from American Heart Association.

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Cite This Study

Gutor et al. (Fri,) studied this question.

synapsesocial.com/papers/6a0d5064f03e14405aa9c311 https://doi.org/https://doi.org/10.1093/ajrccm/aamag162.5911

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