Affiliation:
1. State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China;
2. Department of Cardiology, Geisinger Medical Center, Danville, Pennsylvania
3. Department of Respiratory Diseases, The Affiliated Hospital of Inner Mongolia Medical University Hohhot, Inner Mongolia, China; and
4. Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona, Tucson, Arizona;
5. Division of Pulmonary Medicine, The People's Hospital of Inner Mongolia, Hohhot, Inner Mongolia, China;
Abstract
Our laboratory previously showed that sodium tanshinone IIA sulfonate (STS) inhibited store-operated Ca2+ entry (SOCE) through store-operated Ca2+ channels (SOCC) via downregulating the expression of transient receptor potential canonical proteins (TRPC), which contribute to the formation of SOCC (Wang J, Jiang Q, Wan L, Yang K, Zhang Y, Chen Y, Wang E, Lai N, Zhao L, Jiang H, Sun Y, Zhong N, Ran P, Lu W. Am J Respir Cell Mol Biol 48: 125–134, 2013). The detailed molecular mechanisms by which STS inhibits SOCE and downregulates TRPC, however, remain largely unknown. We have previously shown that, under hypoxic conditions, inhibition of protein kinase G (PKG) and peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling axis results in the upregulation of TRPC (Wang J, Yang K, Xu L, Zhang Y, Lai N, Jiang H, Zhang Y, Zhong N, Ran P, Lu W. Am J Respir Cell Mol Biol 49: 231–240, 2013). This suggests that strategies targeting the restoration of this signaling pathway may be an effective treatment strategy for pulmonary hypertension. In this study, our results demonstrated that STS treatment can effectively prevent the hypoxia-mediated inhibition of the PKG-PPAR-γ signaling axis in rat distal pulmonary arterial smooth muscle cells (PASMCs) and distal pulmonary arteries. These effects of STS treatment were blocked by pharmacological inhibition or specific small interfering RNA knockdown of either PKG or PPAR-γ. Moreover, targeted PPAR-γ agonist markedly enhanced the beneficial effects of STS. These results comprehensively suggest that STS treatment can prevent hypoxia-mediated increases in intracellular calcium homeostasis and cell proliferation, by targeting and restoring the hypoxia-inhibited PKG-PPAR-γ signaling pathway in PASMCs.
Funder
Foundation for the National Institutes of Health (FNIH)
National Natural Science Foundation of China (NSFC)
China Scholarship Council (CSC)
Publisher
American Physiological Society
Cited by
30 articles.
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