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Cytokines decrease sGC in pulmonary artery smooth muscle cells via NO-dependent and NO-independent mechanisms
1Cardiovascular Research Center and Arthritis Unit, Massachusetts General Hospital, and Departments of Medicine and Anesthesia, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
American Journal of Physiology. Lung Cellular and Molecular Physiology
|February 13, 2001
Summary
Cytokines decrease soluble guanylate cyclase (sGC) expression in pulmonary artery smooth muscle cells (PASMC) via nitric oxide (NO)-dependent and independent pathways. This impacts NO-stimulated sGC activity.
Area of Science:
- Pulmonary vascular research
- Cellular signaling
- Molecular biology
Background:
- Cytokines induce nitric oxide (NO) production in rat pulmonary artery smooth muscle cells (rPASMC) via NO synthase 2 (NOS2).
- NO activates soluble guanylate cyclase (sGC), crucial for cGMP synthesis.
- Prolonged NO exposure reduces sGC subunit expression in rPASMC.
Purpose of the Study:
- To investigate if endogenously produced NO is sufficient to decrease sGC expression in rPASMC.
- To elucidate the mechanisms by which cytokines affect sGC expression.
Main Methods:
- Treatment of rPASMC with cytokines (IL-1beta, TNF-alpha) and inhibitors (NOS2 inhibitor, sGC inhibitor).
- Measurement of NOS2 and sGC subunit mRNA and protein levels.
- Assessment of NO-stimulated sGC enzyme activity.
- Experiments using PASMC from NOS2-deficient mice.
Main Results:
- Cytokines increased NOS2 mRNA and decreased sGC subunit mRNA and protein levels in rPASMC.
- Cytokine exposure reduced NO-stimulated sGC enzyme activity.
- NOS2 and sGC inhibitors partially prevented cytokine-induced decreases in sGC mRNA.
- Cytokines decreased sGC subunit mRNA levels in PASMC from NOS2-deficient mice, indicating NO-independent effects.
Conclusions:
- Endogenous NO and cGMP levels in cytokine-exposed PASMC are sufficient to reduce sGC subunit mRNA.
- Cytokines can decrease sGC subunit mRNA through both NO-dependent and NO-independent mechanisms.
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