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Therapeutic strategies utilizing SDF-1α in ischaemic cardiomyopathy
Oliver J Ziff1, Daniel I Bromage1, Derek M Yellon1
1The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, 67 Chenies Mews, London WC1E 6HX, UK.
Insights
Stem cell recruitment via the SDF-1α/CXCR4 pathway aids heart repair after myocardial infarction (MI). Therapeutic strategies targeting this pathway may improve cardiac function, but optimal timing and SDF-1α activity require further investigation.
Area of Science:
- Cardiovascular biology and regenerative medicine.
- Molecular mechanisms of cardiac repair.
- Biomarker discovery for heart failure.
Background:
- Heart failure prevalence is rising globally, necessitating improved treatments for myocardial infarction (MI).
- Stem cell mobilization to the injured heart via homing signals is crucial for cardiac repair.
- The SDF-1α/CXCR4 axis plays a key role in stem cell recruitment and cardiomyocyte survival post-MI.
Purpose of the Study:
- To review the therapeutic potential of the SDF-1α/CXCR4 pathway in myocardial infarction.
- To assess strategies aimed at enhancing SDF-1α signaling or prolonging its activity.
- To highlight SDF-1α as a potential confounder in DPP4 inhibitor studies.
Main Methods:
- Literature review of studies investigating SDF-1α, CXCR4, and stem cell homing in the context of MI.
- Analysis of current therapeutic approaches targeting the SDF-1α/CXCR4 pathway.
- Evaluation of diagnostic limitations in measuring active SDF-1α.
Main Results:
- CXCR4 activation promotes stem cell migration and cardiomyocyte survival, leading to reduced infarct size and improved cardiac function.
- The endogenous timing of SDF-1α release and CXCR4 upregulation may be suboptimal for therapeutic benefit.
- Current assays cannot differentiate active SDF-1α from DPP4-inactivated forms, complicating therapeutic assessment.
Conclusions:
- Targeting the SDF-1α/CXCR4 pathway offers a promising strategy for cardiac repair after MI.
- Further research is needed to optimize the therapeutic window and overcome limitations in SDF-1α measurement.
- SDF-1α should be considered a critical factor in studies involving DPP4 inhibitors for cardiovascular conditions.
Abstract:
Heart failure is rapidly increasing in prevalence and will redraw the global landscape for cardiovascular health. Alleviating and repairing cardiac injury associated with myocardial infarction (MI) is key to improving this burden. Homing signals mobilize and recruit stem cells to the ischaemic myocardium where they exert beneficial paracrine effects. The chemoattractant cytokine SDF-1α and its associated receptor CXCR4 are upregulated after MI and appear to be important in this context. Activation of CXCR4 promotes both cardiomyocyte survival and stem cell migration towards the infarcted myocardium. These effects have beneficial effects on infarct size, and left ventricular remodelling and function. However, the timing of endogenous SDF-1α release and CXCR4 upregulation may not be optimal. Furthermore, current ELISA-based assays cannot distinguish between active SDF-1α, and SDF-1α inactivated by dipeptidyl peptidase 4 (DPP4). Current therapeutic approaches aim to recruit the SDF-1α-CXCR4 pathway or prolong SDF-1α life-time by preventing its cleavage by DPP4. This review assesses the evidence supporting these approaches and proposes SDF-1α as an important confounder in recent studies of DPP4 inhibitors.