The severity of coronavirus 2019 infection (COVID-19) is determined by the presence of pneumonia, severe acute respiratory distress syndrome (SARS-CoV-2), myocarditis, microvascular thrombosis and/or cytokine storms, all of which involve underlying inflammation. A principal defence against uncontrolled inflammation, and against viral infection in general, is provided by T regulatory lymphocytes (Tregs). Treg levels have been reported to be low in many COVID-19 patients and can be increased by vitamin D supplementation. Low vitamin D levels have been associated with an increase in inflammatory cytokines and a significantly increased risk of pneumonia and viral upper respiratory tract infections. Vitamin D deficiency is associated with an increase in thrombotic episodes, which are frequently observed in COVID-19. Vitamin D deficiency has been found to occur more frequently in patients with obesity and diabetes. These conditions are reported to carry a higher mortality in COVID-19. If vitamin D does in fact reduce the severity of COVID-19 in regard to pneumonia/ARDS, inflammation, inflammatory cytokines and thrombosis, it is our opinion that supplements would offer a relatively easy option to decrease the impact of the pandemic.

Abstract-AMP activated protein kinase (AMPK) plays an important role in regulating myocardial metabolism and protein synthesis. Activation of AMPK attenuates hypertrophy in cultured cardiac myocytes, but the role of AMPK in regulating the development of myocardial hypertrophy in response to chronic pressure overload is not known. To test the hypothesis that AMPK␣2 protects the heart against systolic overload-induced ventricular hypertrophy and dysfunction, we studied the response of AMPK␣2 gene deficient (knockout [KO]) mice and wild-type mice subjected to 3 weeks of transverse aortic constriction (TAC). Although AMPK␣2 KO had no effect on ventricular structure or function under control conditions, AMPK␣2 KO significantly increased TAC-induced ventricular hypertrophy (ventricular mass increased 46% in wild-type mice compared with 65% in KO mice) while decreased left ventricular ejection fraction (ejection fraction decreased 14% in wild-type mice compared with a 43% decrease in KO mice). AMPK␣2 KO also significantly exacerbated the TAC-induced increases of atrial natriuretic peptide, myocardial fibrosis, and cardiac myocyte size. AMPK␣2 KO had no effect on total S6 ribosomal protein (S6), p70 S6 kinase, eukaryotic initiation factor 4E, and 4E binding protein-1 or their phosphorylation under basal conditions but significantly augmented the TAC-induced increases of p-p70 S6 kinase Thr389 , p-S6 Ser235 , and p-eukaryotic initiation factor 4E Ser209 . AMPK␣2 KO also enhanced the TAC-induced increase of p-4E binding protein-1Thr46 to a small degree and augmented the TAC-induced increase of p-Akt Ser473 . These data indicate that AMPK␣2 exerts a cardiac protective effect against pressure-overloadinduced ventricular hypertrophy and dysfunction. Key Words: hypertrophy Ⅲ congestive heart failure Ⅲ mTOR I ncreases of cardiac work resulting from systolic overload necessitate an increase of ATP use in proportion to the increase in left ventricular (LV) systolic wall stress. 1,2 In response to chronic systolic overload, cardiac myocyte hypertrophy occurs, characterized by increased protein synthesis, whereas myocardial oxygen consumption and carbon substrate use are increased to accommodate the need for increased energy availability. This initially occurs with no change in high energy phosphate levels, but with the development of pathological hypertrophy and congestive heart failure, ATP levels fall and cytosolic free ADP levels increase (as indicated by a decrease of the myocardial phosphocreatine:ATP ratio). 2,3 In this situation, the adenylate kinase reaction can catalyze the reaction of 2 molecules of ADP to produce 1 molecule of ATP and 1 molecule of AMP. An increased AMP:ATP ratio results in activation of the energy stress sensor known as AMP activated protein kinase (AMPK).AMPK is composed of 1 catalytic ␣ subunit (either ␣1 or ␣2) and 2 regulatory subunits (␤ and ␥). AMPK␣2 is the dominant catalytic subunit in the heart, 3,4 where it is predominantly expressed in cardiac myocytes. AMPK is activated by metabolic stres...

Objectives The objective of this study was to identify the role of dimethylarginine dimethylaminohydrolase-1 (DDAH1) in degrading the endogenous NOS inhibitors ADMA and L-NMMA. Methods and results We generated a global-DDAH1 gene deficient (DDAH1−/−) mouse strain to examine the role of DDAH1 in ADMA and L-NMMA degradation, and the physiological consequences of loss of DDAH1. Plasma and tissue ADMA and L-NMMA levels in DDAH1−/− mice were several fold higher than in wild type mice, but growth and development of these DDAH1−/− mice was similar to their wild type littermates. Although the expression of DDAH2 was unaffected, DDAH activity was undetectable in all tissues tested. These findings indicate that DDAH1 is the critical enzyme for ADMA and L-NMMA degradation. Blood pressure was ~20 mmHg higher in the DDAH1−/− mice than in wild type mice, but no other cardiovascular phenotype was found under unstressed conditions. Crossing DDAH1+/− male with DDAH1+/− female mice yielded DDAH1+/+ mice, DDAH1+/− mice and DDAH1−/− mice at anticipated ratios of 1:2:1, indicating that DDAH1 is not required for embryonic development in this strain. Conclusions Our findings indicate that DDAH1 is required for metabolizing ADMA and L-NMMA in vivo, while DDAH2 had no detectable role for degrading ADMA and L-NMMA.