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Objective: To observe the relationship between murine double minute 2 (mdm2) expression and AngII and ceramide induced human umbilical endothelial cells apoptosis., Method: Human umbilical endothelial cells (ECs) were cultured in vitro and treated with angiotensin II alone or in combination with losartan (an inhibitor of AT1), PD123319 (an inhibitor of AT2) and FB1 (an inhibitor of ceramidase) respectively. ECs were also treated with different doses of C2-ceramide. The apoptosis of ECs was detected with Tunel, the mdm2 mRNA and protein expressions were measured with reverse transcription-polymerase chain reaction (RT-PCR) and Western blot., Results: PD123319 and FB1 but not losartan inhibited AngII induced ECs apoptosis and down-regulated the AngII induced increased mdm2 expressions. C2-ceramide also induces ECs apoptosis and down-regulated mdm2 expressions at protein and mRNA levels in a dose-dependent manner., Conclusions: AngII binding with AT2 induces ECs apoptosis via ceramide. AngII and ceramide induce EC apoptosis by inhibiting mdm2.

Angiotensin II (ANG II) can activate the mitogen-activated protein kinases (MAPKs) and stress-activated protein kinases in several cell types. We have previously shown that the 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism is a mediator of ANG II-induced aldosterone synthesis in adrenal glomerulosa cells. To evaluate the role of MAPK activation in ANG II and the effects of LO on aldosterone synthesis, experiments were performed using the human adrenocortical cell line H295R, which secretes aldosterone in response to ANG II. MAPK activities were determined by Western immunoblotting using specific antibodies to their activated phosphorylated forms. ANG II led to a dose-dependent increase in extracellular signal-regulated kinase (ERK1/2) activity in these cells, with a peak at 5 min and lasting up to 3 h. The effects of ANG II were blocked by the ANG-II Type 1 receptor antagonist losartan. A specific 12-LO product, 12(S)-hydroxyeicosatetraenoic acid (12-HETE), had no direct effect on ERK activity. However, both ANG II and 12-HETE led to significant dose-dependent increases in p38 MAPK activity with peak effects at 5 min. By contrast, the 15-LO product, 15-HETE, had no effect on p38 MAPK activity. Furthermore, two dissimilar 12-LO inhibitors, CDC and baicalein, blocked ANG II-induced p38 MAPK activation. ANG II significantly increased aldosterone release, and this effect was inhibited by the LO inhibitor baicalein, as well as a specific p38 MAPK inhibitor, SB202190, but not by PD098059, a specific inhibitor of the ERK activator MEK. In summary, in H295R cells, ANG II activated ERK and p38 MAPKs, ANG II-induced p38 MAPK was mediated by 12-LO activation, and ANG II-induced aldosterone synthesis was prevented by 12-LO- and p38 MAPK-specific inhibitors. These results suggest, for the first time, that activation of p38 MAPK, either directly or via LO activation, participates in aldosterone's stimulatory effects of ANG II in adrenal cells.

Objective: Diabetes is one of the most distinct comorbidities of COVID-19. Here, we describe the clinical characteristics of and outcomes in patients with diabetes in whom COVID-19 was confirmed or clinically diagnosed (with typical features on lung imaging and symptoms) and their association with glucose-lowering or blood pressure-lowering medications.Research Design and Methods: In this retrospective study involving 904 patients with COVID-19 (136 with diabetes, mostly type 2 diabetes), clinical and laboratory characteristics were collected and compared between the group with diabetes and the group without diabetes, and between groups taking different medications. Logistic regression was used to explore risk factors associated with mortality or poor prognosis.Results: The proportion of comorbid diabetes is similar between cases of confirmed and of clinically diagnosed COVID-19. Risk factors for higher mortality of patients with diabetes and COVID-19 were older age (adjusted odds ratio [aOR] 1.09 [95% CI 1.04, 1.15] per year increase; P = 0.001) and elevated C-reactive protein (aOR 1.12 [95% CI 1.00, 1.24]; P = 0.043). Insulin usage (aOR 3.58 [95% CI 1.37, 9.35]; P = 0.009) was associated with poor prognosis. Clinical outcomes of those who use an ACE inhibitor (ACEI) or angiotensin II type-I receptor blocker (ARB) were comparable with those of patients who do not use ACEI/ARB among COVID-19 patients with diabetes and hypertension.Conclusions: C-reactive protein may help to identify patients with diabetes who are at greater risk of dying during hospitalization. Older patients with diabetes were prone to death related to COVID-19. Attention needs to be paid to patients with diabetes and COVID-19 who use insulin. ACEI/ARB use showed no significant impact on patients with diabetes and hypertension who have COVID-19. [ABSTRACT FROM AUTHOR]