Inhibition of HDAC activity result in the early recruitment of reparative CD45/CD11b/CD206 macrophages in the post-MI heart and correlates with improved ventricular function and remodeling. This work identifies a very promising therapeutic opportunity to manage macrophage phenotype and enhance resolution of inflammation in the post-MI heart.
Histone deacetylases (HDACs) play integral roles in many cardiovascular biological processes ranging from transcriptional and translational regulation to protein stabilization and localization. There are 18 known HDACs categorized into 4 classes that can differ on the basis of substrate targets, subcellular localization, and regulatory binding partners. HDACs are classically known for their ability to remove acetyl groups from histone and nonhistone proteins that have lysine residues. However, despite their nomenclature and classical functions, discoveries from many research groups over the past decade have suggested that nondeacetylase roles exist for class IIa HDACs. This is not surprising given that class IIa HDACs have, for example, relatively poor deacetylase capabilities and are often shuttled in and out of nuclei upon specific pathological and nonpathological cardiac events. This review aims to consolidate and elucidate putative nondeacetylase roles for class IIa HDACs and, where possible, highlight studies that provide evidence for their noncanonical roles, especially in the context of cardiovascular maladies. There has been great interest recently in exploring the pharmacological regulators of HDACs for use in therapeutic interventions for treating cardiovascular diseases and inflammation. Thus it is of interest to earnestly consider nonenzymatic and or nondeacetylase roles of HDACs that might be key in potentiating or abrogating pathologies. These noncanonical HDAC functions may possibly yield new mechanisms and targets for drug discovery.
Cannabis and its natural derivatives have emerged as promising therapeutics for multiple pathological and nonpathological medical conditions. For example, cannabinoids, the most popular and biologically active chemicals in cannabis, aid in many clinical ailments, including pain, inflammation, epilepsy, sleep disturbances or insomnia, multiple sclerosis, anorexia, schizophrenia, neurodegenerative diseases, antinausea, and most importantly, cancer. Despite the comprehensive benefits, certain aspects of cannabis present unique challenges in the medical cannabis landscape. Recent studies have highlighted the inherent challenges associated with cannabinoids' formulation like low solubility, rapid metabolism, poor bioavailability, and erratic pharmacokinetics – all of which contribute to the limited efficacy of cannabinoids. Several efforts are underway to address the bottlenecks and modify the formulations along with the delivery systems to achieve greater solubility/bioavailability, potency, and efficacy in treatment settings while minding the necessary standards for purity associated with the pharmaceutical industry. The current article presents a perspective on (1) a working knowledge of cannabinoids and their mechanisms of action, (2) the landscape of using medicinal cannabis for cancer-related medical conditions along with adversities, (3) current approaches, formulations, and challenges in medicinal cannabis delivery systems (oral, transdermal, pulmonary, and transmucosal), and lastly, (4) emerging approaches to improve delivery systems.
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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