DPP4 and ACE2 in diabetes and COVID-19: Therapeutic targets for cardiovascular complications?

COVID-19 outbreak, caused by severe acute respiratory syndrome (SARS)-CoV-2 coronavirus has become an urgent health and economic challenge. Diabetes is a risk factor for severity and mortality of COVID-19. Recent studies support that COVID-19 has effects beyond the respiratory tract, with vascular complications arising as relevant factors worsening its prognosis, then making patients with previous vascular disease more prone to severity or fatal outcome. Angiotensin-II converting enzime-2 (ACE2) has been proposed as preferred receptor for SARS-CoV-2 host infection, yet specific proteins participating in the virus entry are not fully known. SARS-CoV-2 might use other co-receptor or auxiliary proteins allowing virus infection. In silico experiments proposed that SARS-CoV-2 might bind dipeptidyl peptidase 4 (DPP4/CD26), which was established previously as receptor for MERS-CoV. The renin–angiotensin–aldosterone system (RAAS) component ACE2 and DPP4 are proteins dysregulated in diabetes. Imbalance of the RAAS and direct effect of soluble DPP4 exert deleterious vascular effects. We hypothesize that diabetic patients might be more affected by COVID-19 due to increased presence ACE2 and DPP4 mediating infection and contributing to a compromised vasculature. Here, we discuss the role of ACE2 and DPP4 as relevant factors linking the risk of SARS-CoV-2 infection and severity of COVID-19 in diabetic patients and present an outlook on therapeutic potential of current drugs targeted against RAAS and DPP4 to treat or prevent COVID-19-derived vascular complications. Diabetes affects more than 400 million people worldwide, thus better understanding of how they are affected by COVID-19 holds an important benefit to fight against this disease with pandemic proportionsIV is the recipient of a FPU fellowship (FPU16/02612). TR and JE are supported by KomIT-Center of Competence for Innovative Diabetes Therapy- funded by EFRE-NRW. CP and CS-F are supported by a grant from Plan Nacional de I+D (SAF2017-84776-R

Budget Processes: Theory and Experimental Evidence

This paper studies budget processes, both theoretically and experimentally. We compare the outcomes of bottom-up and top-down budget processes. It is often presumed that a top-down budget process leads to a smaller overall budget than a bottom-up budget process. Ferejohn and Krehbiel (1987) showed theoretically that this need not be the case. We test experimentally the theoretical predictions of their work. The evidence from these experiments lends strong support to their theory, both at the aggregate and the individual subject level

Insulin action on cardiac glucose transport: studies on the role of protein kinase C

AbstractIsolated ventricular cardiomyocytes from adult rat have been used to elucidate a possible relationship between protein kinase C (PKC) and the stimulatory action of insulin on cardiac glucose transport. Cells were incubated in the presence of either insulin or phospholipase C from Clostridium perfringens (PLC-Cp) and intracellular sn-1,2-diacylglycerol (DAG) levels and initial rates of 3-O-methylglucose transport were determined. Insulin had no effect on the DAG mass level, whereas it was elevated by PLC-Cp to 200% of control. Under these conditions the hormone produced a 2.7-fold stimulation of glucose transport with no significant effect of PLC-Cp. Insulin was unable to produce a redistribution of PKC, whereas phorbol 12-myristate 13-acetate (PMA) increased membrane associated PKC twofold. The PKC inhibitors tamoxifen and staurosporine did not interfere with glucose transport stimulation by insulin. Furthermore, cells treated with PMA exhibited unaltered basal and maximally insulin stimulated rates of glucose transport. In contrast, at physiological concentrations of insulin the stimulatory action of the hormone was significantly reduced. We conclude from our data that PKC is not involved in insulin action on cardiac glucose transport. However, activation of this enzyme may lead to a modified insulin sensitivity of the cardiac cell

Protease-Activated Receptor 2 Promotes Pro-Atherogenic Effects through Transactivation of the VEGF Receptor 2 in Human Vascular Smooth Muscle Cells

BACKGROUND: Obesity is associated with impaired vascular function. In the cardiovascular system, protease-activated receptor 2 (PAR2) exerts multiple functions such as the control of the vascular tone. In pathological conditions, PAR2 is related to vascular inflammation. However, little is known about the impact of obesity on PAR2 in the vasculature. Therefore, we explored the role of PAR2 as a potential link between obesity and cardiovascular diseases. METHODS: C57BL/6 mice were fed with either a chow or a 60% high fat diet for 24 weeks prior to isolation of aortas. Furthermore, human coronary artery endothelial cells (HCAEC) and human coronary smooth muscle cells (HCSMC) were treated with conditioned medium obtained from in vitro differentiated primary human adipocytes. To investigate receptor interaction vascular endothelial growth factor receptor 2 (VEGFR2) was blocked by exposure to calcium dobesilate and a VEGFR2 neutralization antibody, before treatment with PAR2 activating peptide. Student's t-test or one-way were used to determine statistical significance. RESULTS: Both, high fat diet and exposure to conditioned medium increased PAR2 expression in aortas and human vascular cells, respectively. In HCSMC, conditioned medium elicited proliferation as well as cyclooxygenase 2 induction, which was suppressed by the PAR2 antagonist GB83. Specific activation of PAR2 by the PAR2 activating peptide induced proliferation and cyclooxygenase 2 expression which were abolished by blocking the VEGFR2. Additionally, treatment of HCSMC with the PAR2 activating peptide triggered VEGFR2 phosphorylation. CONCLUSION: Under obesogenic conditions, where circulating levels of pro-inflammatory adipokines are elevated, PAR2 arises as an important player linking obesity-related adipose tissue inflammation to atherogenesis. We show for the first time that the underlying mechanisms of these pro-atherogenic effects involve a potential transactivation of the VEGFR2 by PAR2

A Practical Approach for Generic Bootkit Detection and Prevention

Bootkits are still the most powerful tool for attackers to stealthily infiltrate computer systems. In this paper we present a novel approach to detect and prevent bootkit attacks during the infection phase. Our approach relies on emulation and monitoring of the system’s boot process. We present results of a preliminary evaluation on our approach using a Windows system and the leaked Carberp bootkit