Cardiovascular & Lipid Disorders

Muhammad Ashraf

Muhammad Ashraf, PhD

Pathology & Lab Med

Professor

Research Summary

Dr. Ashraf’s research is focused on molecular and cellular mechanisms of myocardial ischemic injury and identifying therapies that prevent cell damage/death in the ischemic heart. The current therapeutic modalities fail to address the root cause of the problem which is characterized by compromised blood flow to the heart due to coronary artery occlusion and irreversible cardiomyocytes loss. To this end, he is applying two approaches in the research laboratory. The first approach requires careful study of the heart’s intrinsic defense mechanisms. When a mild heart attack occurs, the heart attempts to ward off the serious attack and uses endogenous systems and defenses to minimize cell and tissue damage. This is particularly true when brief reversible ischemic episodes followed by restoration of coronary blood supply precede a heart attack.The understanding of this phenomenon, referred as ‘preconditioning’, will allow identification of the potential approaches through which therapies could be designed. The cardiac protection associated with this ‘preconditioning’ is so powerful that no other pharmacological agent to date has matched its beneficial effect.The major significance of his work is that the effects of ischemic preconditioning can be mimicked via pharmacological interventions using mitochondrial potassium channel openers. Recently he advanced the concept of chronic preconditioning of hearts against lethal ischemia so that the heart can be protected for extended period of time in case the patient suffers an unexpected heart attack. He has also pioneered the novel concept of exploiting the cytoprotective effects of preconditioning to alleviate the problem of donor cell attrition during the acute phase after stem cell engraftment in the infarcted heart

In second line of research, the dead heart muscle after myocardial infarction is being regenerated by bone marrow or cardiac stem cell engraftment.This research is designed to address feasibility of heart cell regeneration in both young and old hearts.Once the heart attack kills the cardiac cells, the damaged muscle is replaced with scar tissue, which impairs the pump function of the heart. Bone marrow cells or cardiac stem cells are multipotent and can be directed to differentiate into desired cell types and given the proper milieu, these cells have a potential in treating a failing heart. Dr Ashraf’s research group has adopted a novel approach of combining stem cell transplantation with therapeutic gene delivery via genetic modulation of the donor cells prior to transplantation. This includes a multimodal approach of combining stem cell transplantation with the delivery of therapeutic genes including Akt, HGF, IGF, angiopoietin-1 and stromal cell deived factor-1α, Gata-4

 

Recent Publications

 

Ahmad N, Wang Y, Ali AK, Ashraf M. Long-acting phosphodiesterase-5 inhibitor, tadalafil, induces sustained cardioprotection against lethal ischemic injury. Am J Physiol Heart Circ Physiol. 2009 Jul;297(1):H387-91. Epub 2009 May 8. PubMedPMID: 19429825; PubMed Central PMCID: PMC2711726.

Lu G, Haider HK, Jiang S, Ashraf M. Sca-1+ stem cell survival and engraftment in the infarcted heart: dual role for preconditioning-induced connexin-43.Circulation. 2009 May 19;119(19):2587-96. Epub 2009 May 4. PubMed PMID: 19414636.

Kim HW, Haider HKh, Jiang S, Ashraf M. Ischemic preconditioning augments survival of stem cells via MIR-210 expression by targeting caspase-8 associated protein 2. J Biol. Chem, 2009 (Available on line, In Press).

Afzal RM , Haider Kh ; Idris NM, Jiang S, MD; Ahmed R PH ; Ashraf M. Preconditioning Promotes Survival and Angiomyogenic Potential of MSCs in the Infarcted Heart via Nuclear Factor-κB Signaling. Antioxidants & Redox Signaling,2009 (Available on line,In Press)

Haider HKh, Jiang S, Idris NM, Ashraf M. IGF-1-overexpressing mesenchymal stemcells accelerate bone marrow stem cell mobilization via paracrine activation ofSDF-1alpha/CXCR4 signaling to promote myocardial repair. Circ Res. 2008 Nov21;103(11):1300-8. Epub 2008 Oct 23. PubMed PMID: 18948617.

 

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