Editors' ChoiceHeart Disease

A mighty "MyD" guardian of heart function

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Science Translational Medicine  18 Feb 2015:
Vol. 7, Issue 275, pp. 275ec28
DOI: 10.1126/scitranslmed.aaa9139

The moment a coronary artery becomes occluded, the race is on to restore blood flow to ischemic myocardium as fast as possible to preserve maximal viability of cardiomyocytes. However, even with reperfusion therapies such as thrombolysis or coronary stenting, substantial myocardial damage can ensue and lead to scar formation and heart failure. Therefore, in addition to prompt revascularization, the development of adjunctive pharmacologic strategies that protect ischemic cardiomyocytes is urgently needed to optimize myocardial recovery during a heart attack. Motivated by this major unmet need, Korf-Klingebiel et al. have discovered a new secreted protein that has myoprotective properties and may have potential for drug development.

The authors hypothesized that the beneficial effects of autologous bone marrow cell (BMC) therapy seen in clinical trials of heart attack patients might be mediated by paracrine factors secreted by BMCs. They performed gene expression microarrays in patient-derived BMCs and identified 42 genes that were poorly characterized and encoded putative secreted proteins. They then expressed each of these 42 genes in HEK293 cells and screened the supernatants for their ability to protect cultured cardiomyocytes from ischemia and to promote angiogenesis in cultured endothelial cells. They identified a secreted protein, which they named MYDGF, and found that it had potent myoprotective and pro-angiogenic effects in their screen. The abundance of MYDGF was shown to be increased in the infarcted human myocardium, and mice that were genetically deficient in MYDGF were more susceptible to cardiac ischemia-reperfusion injury. MYGDF was found to be robustly expressed in bone marrow–derived monocytes and macrophages, and bone marrow transplantation experiments confirmed that BMC-derived MYDGF was necessary and sufficient to exert cardioprotective effects during ischemia-reperfusion in mice. Finally, treatment of mice with recombinant MYGDF exerted myoprotective effects, even when given 6 hours after reperfusion, suggesting therapeutic potential even when given late.

This study identifies a new myeloid-derived secreted protein that acts in a paracrine manner to protect cardiomyocytes from ischemic injury and preserve cardiac function after a heart attack. Further studies that define the precise mechanisms by which MYDGF is produced and secreted by myeloid cells and triggers downstream signaling events in myocardial tissue should provide important insights into its therapeutic potential, not only during myocardial infarction, but potentially in a host of other cardiovascular or ischemic conditions.

M. Korf-Klingebiel et al., Myeloid-derived growth factor (C19orf10) mediates cardiac repair following myocardial infarction. Nat. Med. 21, 140–149 (2015).[Abstract]

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