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  3. Zinc-mediated activation of CREB pathway in proliferation of pulmonary artery smooth muscle cells in pulmonary hypertension

Zinc-mediated activation of CREB pathway in proliferation of pulmonary artery smooth muscle cells in pulmonary hypertension

  • Cell Commun Signal. 2021 Oct 11;19(1):103. doi: 10.1186/s12964-021-00779-y.
Genfa Xiao 1 2 3 4 5,  Guili Lian 6,  Tingjun Wang 7 6 8 9,  Weixiao Chen 6,  Wei Zhuang 6,  Li Luo 7 6 8 9,  Huajun Wang 6,  Liangdi Xie 10 11 12 13
Affiliations

Affiliations

  • 1 Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China. iesvev1986@foxmail.com.
  • 2 Department of Cardiology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, People's Republic of China. iesvev1986@foxmail.com.
  • 3 Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, Gannan Medical University, Ganzhou, 341000, People's Republic of China. iesvev1986@foxmail.com.
  • 4 Gannan Branch Center of National Geriatric Disease Clinical Medical Research Center, Gannan Medical University, Ganzhou, 341000, People's Republic of China. iesvev1986@foxmail.com.
  • 5 Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China. iesvev1986@foxmail.com.
  • 6 Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China.
  • 7 Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China.
  • 8 Branch of National Clinical Research Center for Aging and Medicine, Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
  • 9 Fujian Provincial Clinical Research Center for Geriatric Hypertension Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
  • 10 Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China. ldxield@163.com.
  • 11 Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China. ldxield@163.com.
  • 12 Branch of National Clinical Research Center for Aging and Medicine, Fujian Province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China. ldxield@163.com.
  • 13 Fujian Provincial Clinical Research Center for Geriatric Hypertension Disease, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China. ldxield@163.com.
PMID: 34635097 DOI: 10.1186/s12964-021-00779-y
Abstract

Background: Transcription factor CREB is involved in the development of pulmonary hypertension (PH). However, little is known about the role and regulatory signaling of CREB in PH.

Methods: A series of techniques, including bioinformatics methods, western blot, cell proliferation and luciferase reporter assay were used to perform a comprehensive analysis of the role and regulation of CREB in proliferation of pulmonary artery smooth muscle cells (PASMCs) in PH.

Results: Using bioinformatic analysis of the differentially expressed genes (DEGs) identified in the development of monocrotaline (MCT)- and hypoxia-induced PH, we found the overrepresentation of CRE-containing DEGs. Western blot analysis revealed a sustained increase in total- and phosphorylated-CREB in PASMCs isolated from rats treated with MCT. Similarly, an enhanced and prolonged serum-induced CREB phosphorylation was observed in hypoxia-pretreated PASMCs. The sustained CREB phosphorylation in PASMCs may be associated with multiple protein kinases phosphorylated CREB. Additionally, hierarchical clustering analysis showed reduced expression of the majority of CREB phosphatases in PH, including regulatory subunits of PP2A, Ppp2r2c and Ppp2r3a. Cell proliferation analysis showed increased PASMCs proliferation in MCT-induced PH, an effect relied on CREB-mediated transcriptional activity. Further analysis revealed the raised intracellular labile zinc possibly from ZIP12 was associated with reduced phosphatases, increased CREB-mediated transcriptional activity and PASMCs proliferation.

Conclusions: CREB pathway was overactivated in the development of PH and contributed to PASMCs proliferation, which was associated with multiple protein kinases and/or reduced CREB phosphatases and raised intracellular zinc. Thus, this study may provide a novel insight into the CREB pathway in the pathogenesis of PH. Video abstract.

Keywords

CREB; Intracellular labile zinc; Protein phosphatases; Pulmonary artery smooth muscle cells proliferation; Pulmonary hypertension.

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