Myocardial infarctions (MIs) cause the loss of myocytes due to lack of sufficient oxygenation and latent revascularization. Although the administration of histone deacetylase (HDAC) inhibitors reduces the size of infarctions and improves cardiac physiology in small-animal models of MI injury, the cellular targets of the HDACs, which the drugs inhibit, are largely unspecified. Here, we show that WNT-inducible secreted protein-1 (Wisp-1), a matricellular protein that promotes angiogenesis in cancers as well as cell survival in isolated cardiac myocytes and neurons, is a target of HDACs. Further, Wisp-1 transcription is regulated by HDACs and can be modified by the HDAC inhibitor, suberanilohydroxamic acid (SAHA/vorinostat), after MI injury. We observe that, at 7 days after MI, Wisp-1 is elevated 3-fold greater in the border zone of infarction in mice that experience an MI injury and are injected daily with SAHA, relative to MI alone. Additionally, human coronary artery endothelial cells (HCAECs) produce WISP-1 and are responsive to autocrine WISP-1-mediated signaling, which functionally promotes their proangiogenic behavior. Altering endogenous expression of WISP-1 in HCAECs directly impacts their network density in vitro. Therapeutic interventions after a heart attack define the extent of infarct injury, cell survival, and overall prognosis. Our studies shown here identify a potentially novel cardiac angiokine, Wisp-1, that may contribute to beneficial post-MI treatment modalities.
Introduction: Re-establishing vasculature after a myocardial infarction (MI) may spare cardiomyocytes from death due to lack of sufficient oxygen. WISP-1 -a secreted matricellular protein that regulates angiogenesis in certain cancers- promotes cell survival in isolated cardiomyocytes in vitro . However, the potential role WISP-1 plays post-MI, has not been evaluated. Histone deacetylase inhibition (HDACi) attenuate adverse effects of an MI in small animal models but it is unclear which genes and or targets contribute to this benefit. Our preliminary data shows that Wisp-1 is upregulated 15-fold in response to MI injury compared to sham-operated mice, but is upregulated 45-fold in mice that are subjected to an MI injury and treated with the HDAC inhibitor, Vorinostat. Therefore, we hypothesized that HDACi mediated upregulation of Wisp-1 contributes to beneficial angiogenesis, post-MI . Methods: To test this, we subjected 10-12 week old male mice to ligation of the L.A.D. coronary artery or a sham operation. Mice were injected daily with either DMSO/vehicle, or Vorinostat. Seven days post-MI, mice were euthanized and their heart tissue was assessed for the expression of Wisp-1 and microvasculature. We also assessed the impact of recombinant WISP-1, and respective lentiviral mediated upregulation and shRNA mediated suppression of WISP-1 expression on human coronary artery endothelial cells (HCAECs). Results: In vivo , HDACi mediated upregulation and expression of Wisp-1 /Wisp-1 is observed at the border zone of infarction and its expression is proximal to microvasculature. Recombinant WISP-1 protein promotes expression of pro-angiogenic genes and phenotypic characteristics in HCAECs. Lastly, lentiviral activation and shRNA-targeted suppression of endogenous WISP-1 respectively enhances and reduces endothelial cell network branching in vitro . Conclusion: Therapeutic interventions after a heart attack impact the extent of infarct injury, cell survival and overall prognosis. Our studies shown here identify a novel pro-angiogenic target, Wisp-1, that may be useful in post-MI treatment modalities.
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