Objective-Activation of collagen receptors expressed by smooth muscle cells induces matrix metalloproteinase (MMP) expression. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to interfere with integrin signaling, but their effects on collagen receptor-mediated MMP expression have not been investigated. Methods and Results-In the present study, we show that simvastatin (3 mol/L) reduces MMP1 expression and secretion in human smooth muscle cells cultured on polymerized type I collagen by 39.9Ϯ11.2% and 36.0Ϯ2.3%, respectively. Reduced MMP1 protein levels correlate with a similar decrease in MMP1 promoter activity (Ϫ33.0Ϯ8.9%), MMP1 mRNA levels (Ϫ37.8Ϯ10.5%), and attenuation of smooth muscle cell collagen degradation (Ϫ34.2Ϯ6.1%). Mevalonate, and the isoprenoid derivative geranylgeraniol, precursors of geranylgeranylated proteins, completely prevent the inhibitory effect of simvastatin on MMP1. Moreover, the protein geranylgeranyltransferase inhibitor GGTI-286 significantly decreases MMP1 expression. Retroviral overexpression of dominant-negative mutants of geranylgeranylated Rac1 lead to a reduction of MMP1 protein (Ϫ50.4Ϯ5.4%) and mRNA levels (Ϫ97.9Ϯ1.0%), and knockdown of Rac1 by small interfering RNA downregulates MMP1 expression. Finally, simvastatin reduces GTP-bound Rac1 expression levels in smooth muscle cells cultured on polymerized collagen. T he integrity of interstitial type I collagen in the fibrous cap that covers the atherosclerotic lesions represents a critical factor for the clinical sequelae associated with cardiovascular disease, such as myocardial infarction and stroke. 1,2 Therefore, a pharmacological intervention aimed at inhibiting extracellular matrix degradation may have beneficial effects on the development of atherosclerotic plaques and their stability. Extracellular matrix not only provides a scaffold for mechanical support and tissue organization but also directly alters cell behavior by influencing proliferation, migration, differentiation, and gene expression. For example, smooth muscle cells (SMCs) cultured on polymerized type I collagen show altered expression of a group of genes including matrix metalloproteinase (MMP) 1, type I collagen, and other extracellular matrix components. [3][4][5][6] This 3-dimensional culture system has been developed as an in vitro model that more closely mimics the in vivo extracellular matrix environment surrounding SMCs. 7 In particular, SMC transmembrane adhesion receptors for type I collagen of the integrin family and discoidin domain receptors (DDRs) have been shown to mediate MMP1 upregulation, MMP2 activation, and inhibition of collagen biosynthesis. 8,9 The 3-hydroxy-3-methylglutaryl hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), drugs commonly used to reduce plasma cholesterol levels, have been shown to directly interfere with the major processes of atherogenesis, including SMC proliferation and migration, 10 -12 cholesterol accumulation in macrophages, 13 and endothelial cell activa...

Background: Biomarkers are used for diagnosis, risk stratification and medical decisions. Copeptin and mid-regional proadrenomedullin (MR-proADM) are markers of stress and endothelial function, respectively, which have been studied in pneumonia, sepsis and septic shock. This study aimed to assess whether copeptin and MR-proADM could predict coronavirus disease 2019 in-hospital outcomes, that is multi-system complications, length of stay and mortality.

No abstract

Background Aspartate aminotransferase (AST) is often increased in COVID-19 and, in some studies, AST abnormalities were associated with mortality risk. Methods 2054 hospitalized COVID-19 patients were studied. To identify sources of AST release, correlations between AST peak values and other biomarkers of tissue damage, i.e., alanine aminotransferase (ALT) for hepatocellular damage, creatine kinase (CK) for muscle damage, lactate dehydrogenase for multiorgan involvement, alkaline phosphatase and γ-glutamyltransferase for cholestatic injury, and C-reactive protein (CRP) for systemic inflammation, were performed and coefficients of determination estimated. The role of AST to predict death and intensive care unit admission during hospitalization was also evaluated. All measurements were performed using standardized assays. Results AST was increased in 69% of patients. Increases could be fully explained by summing the effects of hepatocellular injury [AST dependence from ALT, 66.8% [95% confidence interval (CI): 64.5-69.1)] and muscle damage [AST dependence from CK, 42.6% (CI: 39.3-45.8)]. We were unable to demonstrate an independent association of AST increases with worse outcomes. Conclusion The mechanisms for abnormal AST in COVID-19 are likely multifactorial and a status related to tissue suffering could play a significant role. The clinical significance of AST elevations remains unclear.