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Keywords: COVID-19; diabetes; RAGE (receptor for advanced glycation end products); HMGB-1 (high mobility group box 1); pneumonia; coagulation disorders EN COVID-19 diabetes RAGE (receptor for advanced glycation end products) HMGB-1 (high mobility group box 1) pneumonia coagulation disorders 1 6 6 07/20/20 20200714 NES 200714 Introduction The recent looming pandemic of Coronavirus disease 2019 (COVID-19) is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has 80% homology with SARS-CoV-1 and 50% homology with the Middle East respiratory syndrome (MERS) viruses, both pathogens most likely originating from bats ([1]). Rage and its Ligands As Key Regulators of The Innate Immunity and Inflammation and Their Role... RAGE has been named for its ability to bind advanced glycation end products (AGEs) that are found at increased levels in patients with hyperglycemia and contribute to chronic vascular complications of DM patients ([16]). An encouragement to chase this track more in depth comes from the observation that in non-COVID-19 critically ill hyperglycemic patients admitted at ICU, plasma levels of sRAGE are higher in DM vs. non-DM patients, and reduced by intensive insulin therapy only in DM patients ([41]). [Extracted from the article]

G protein-coupled estrogen receptor (GPER) is an estrogen receptor expressed in the cardiovascular system. G1, a selective GPER ligand, exerts cardiovascular effects through activation of the PI3K-Akt pathway and Notch signaling in normotensive animals. Here, we investigated whether the G1/GPER interaction is involved in the limitation of infarct size, and improvement of post-ischemic contractile function in female spontaneous hypertensive rat (SHR) hearts. In this model, we also studied Notch signaling and key components of survival pathway, namely PI3K-Akt, nitric oxide synthase (NOS) and mitochondrial KC-ATP (MitoKATP) channels. Rat hearts isolated from female SHR underwent 30 min of global, normothermic ischemia and 120 min of reperfusion. G1 (10 nM) alone or specific inhibitors of GPER, PI3K/NOS and MitoKATP channels co-infused with G1, just before I/R, were studied. The involvement of Notch1 was studied by Western blotting. Infarct size and left ventricular pressure were measured. To confirm endothelial-independent G1-induced protection by Notch signaling, H9c2 cells were studied with specific inhibitor, N-[N- (3,5 difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT, 5 mM), of this signaling. Using DAPT, we confirmed the involvement of G1/Notch signaling in limiting infarct size in heart of normotensive animals. In the hypertensive model, G1-induced reduction in infarct size and improvement of cardiac function were prevented by the inhibition of GPER, PI3K/NOS, and MitoKATP channels. The involvement of Notch was confirmed by western blot in the hypertensive model and by the specific inhibitor in the normotensive model and cardiac cell line. Our results suggest that GPERs play a pivotal role in mediating preconditioning cardioprotection in normotensive and hypertensive conditions. The G1-induced protection involves Notch1 and is able to activate the survival pathway in the presence of comorbidity. Several pathological conditions, including hypertension, reduce the efficacy of ischemic conditioning strategies. However, G1-induced protection can result in significant reduction of I/R injury also female in hypertensive animals. Further studies may ascertain the clinical translation of the present results. [ABSTRACT FROM AUTHOR]