SERCA2 dysfunction stimulates inflammation and causes pulmonary vascular remodeling by downregulating...

Area of Science:

• Cardiovascular Research
• Pulmonary Medicine
• Cellular Biology

Background:

• Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) dysfunction is linked to pulmonary vascular remodeling.
• Inflammation is a known contributor to pulmonary vascular remodeling.
• The role of SERCA2 dysfunction in pulmonary vascular inflammation was previously unreported.

Purpose of the Study:

• To investigate the contribution of SERCA2 dysfunction to inflammation in pulmonary vascular remodeling.
• To elucidate the molecular mechanisms by which SERCA2 dysfunction induces inflammation.
• To identify potential therapeutic targets for SERCA2 dysfunction-related pulmonary vascular remodeling.

Main Methods:

• Assessment of inflammatory cell infiltration in mice with SERCA2 dysfunction.
• Analysis of SERCA2 dysfunction's effects on inflammatory and oxidative stress markers in pulmonary artery smooth muscle cells (PASMCs).
• Evaluation of therapeutic interventions targeting PPARγ, PGC1α, and ROS.

Main Results:

• SERCA2 dysfunction led to significant inflammatory cell infiltration in mouse lungs.
• In PASMCs, SERCA2 dysfunction downregulated PPARγ, PGC1α, and Nrf2, inducing inflammation and oxidative stress.
• Pioglitazone, nicotinamide riboside, and 4-Hydroxy-TEMPO treatments ameliorated SERCA2 dysfunction-induced pulmonary vascular remodeling.

Conclusions:

• SERCA2 dysfunction directly initiates inflammation, promoting PASMC proliferation, migration, and inflammatory cell recruitment.
• This inflammatory cascade contributes significantly to pulmonary vascular remodeling.
• SERCA2, PPARγ, PGC1α, and ROS represent potential therapeutic targets for pulmonary hypertension.