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Cytoglobin Promotes Cardiac Progenitor Cell Survival against Oxidative Stress via the Upregulation of the NFκB/iNOS
Shuning Zhang1, Xiuchun Li1, Frances L Jourd'heuil1
1Center for Cardiovascular Sciences, Department of Molecular and Cellular Physiology, & Department of Medicine, Albany Medical College, Albany, NY, 12208, USA.
Insights
Cytoglobin (CYGB) enhances human cardiac progenitor cell survival against oxidative stress. This involves nitric oxide production, offering a new target for heart repair therapies.
Area of Science:
- Biomedical Science
- Regenerative Medicine
- Cell Biology
Background:
- Human cardiac stem/progenitor cells (hCPCs) show promise for repairing heart damage.
- Poor survival of transplanted hCPCs limits their therapeutic efficacy.
- Cytoglobin (CYGB) is implicated in nitric oxide (NO) metabolism and cell death regulation.
Purpose of the Study:
- To investigate the role of CYGB in hCPC survival.
- To elucidate the molecular mechanisms by which CYGB influences hCPC fate.
- To explore CYGB as a potential therapeutic target for cardiac regeneration.
Main Methods:
- Molecular techniques to modulate CYGB expression in hCPCs.
- Assessment of hCPC survival under oxidative stress.
- Analysis of antioxidant and anti-apoptotic gene expression.
- Investigation of the CYGB-nitric oxide-NFκB signaling pathway.
Main Results:
- CYGB is expressed in hCPCs and acts as a pro-survival factor.
- Increased CYGB upregulates antioxidant (e.g., Prdx-1, HO-1) and anti-apoptotic (e.g., BCL2) factors.
- CYGB promotes NFκB-dependent iNOS expression and NO production.
- A feedforward loop involving iNOS-derived NO maintains CYGB expression.
Conclusions:
- CYGB plays a critical role in hCPC survival, particularly under oxidative stress.
- The CYGB pathway, involving NO and NFκB signaling, is a key regulator of hCPC fate.
- Targeting the CYGB pathway could enhance the effectiveness of cell-based therapies for ischemic heart disease.
Abstract:
Human cardiac stem/progenitor cells (hCPCs) may serve in regenerative medicine to repair the infarcted heart. However, this approach is severely limited by the poor survival of donor cells. Recent studies suggest that the mammalian globin cytoglobin (CYGB) regulates nitric oxide (NO) metabolism and cell death. In the present study, we found that CYGB is expressed in hCPCs. Through molecular approaches aimed at increasing or decreasing CYGB expression in hCPCs, we found that CYGB functions as a pro-survival factor in response to oxidative stress. This was associated with the upregulation of primary antioxidant systems such as peroxiredoxins-1, heme oxygenase-1, and anti-apoptotic factors, including BCL2, BCL-XL, and MCL1. Most significantly, we established that CYGB increased the expression of NFкB-dependent genes including iNOS, and that iNOS-dependent NO production was required for a feedforward loop that maintains CYGB expression. Our study delineates for the first time a role for a globin in regulating hCPC survival and establishes mechanistic insights in the function of CYGB. It provides a rationale for the exploration of the CYGB pathway as a molecular target that can be used to enhance the effectiveness of cardiac stem/progenitor cell therapy for ischemic heart disease.
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