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Objective:Ischemic heart disease accounts for over 20% of all deaths worldwide. As the global population faces a rising burden of chronic diseases, such as hypertension, hyperlipidemia, and diabetes, the prevalence of heart failure due to ischemic heart disease is estimated to increase. We sought to develop a model that may more accurately identify therapeutic targets to mitigate the development of heart failure following myocardial infarction (MI).Approach:Having utilized fetal large mammalian models of scarless wound healing, we proposed a fetal ovine model of myocardial regeneration after MI.Results:Use of this model has identified critical pathways in the mammalian response to MI, which are differentially activated in the regenerative, fetal mammalian response to MI when compared to the reparative, scar-forming, adult mammalian response to MI.Innovation:While the foundation of myocardial regeneration research has been built on zebrafish and rodent models, effective therapies derived from these disease models have been lacking; therefore, we sought to develop a more representative ovine model of myocardial regeneration after MI to improve the identification of therapeutic targets designed to mitigate the development of heart failure following MI.Conclusions:To develop therapies aimed at mitigating this rising burden of disease, it is critical that the animal models we utilize closely reflect the physiology and pathology we observe in human disease. We encourage use of this ovine large mammalian model to facilitate identification of therapies designed to mitigate the growing burden of heart failure.

A central feature of diabetic (Db) wounds is the persistence of chronic inflammation, which is partly due to the prolonged presence of proinflammatory (M1) macrophages. Using in vivo and in vitro analyses, we have tested the hypothesis that long noncoding RNA GAS5is dysregulated in Db wounds. We have assessed the contribution of GAS5to the M1 macrophage phenotype, as well as the functional consequences of knocking down its expression. We found that expression of GAS5is increased significantly in Db wounds and in cells isolated from Db wounds. Hyperglycemia induced GAS5expression in macrophages in vitro. Overexpression of GAS5in vitro promoted macrophage polarization toward an M1 phenotype by upregulating signal transducer and activator of transcription 1. Of most significance in our judgment, GAS5loss-of-function enhanced Db wound healing. These data indicate that the relative level of long noncoding RNA GAS5in wounds plays a key role in the wound healing response. Reductions in the levels of GAS5in wounds appeared to enhance healing by promoting transition of M1 macrophages to M2 macrophages. Thus, our results suggest that targeting long noncoding RNA GAS5may provide a therapeutic intervention for correcting impaired Db wound healing.

Wound healing is of major clinical concern and is constantly being explored for early restoration and enhanced recovery. While the etiology of the wound healing is multifactorial, high inflammation and increased oxidative stress which results in chronic inflammation, endothelial dysfunction and collagen degradation, delay the overall healing process. Thus, visual sensing of the oxidative stress would be highly informative in the successful implementation of wound healing therapies based on specific requirements. In this study, electrospinning was used to fabricate silk fibroin nanofibrous mats infused with Amplex red capable of detecting hydrogen peroxide, a reactive oxygen molecule. These mats produced a visible change in color with the limit of detection at 1 μM H2O2concentration. In vivostudies carried out in diabetic mice with impaired wounds also displayed a visible change in color of the mats infused with Amplex red within 24 hours. These electrospun silk fibroin nanofibrous Amplex infused mats has the potential to enable a futuristic platform where decisions can be made for enhanced wound healing therapy.