Identification of 18ß-glycyrrhetinic acid as an AGT inhibitor against LPS-induced myocardial dysfunction via high throughput screening.

Sepsis induced myocardial dysfunction (SIMD) is a serious complication of sepsis. There is increasing evidence that the renin-angiotensin system (RAS) is activated in SIMD. Angiotensinogen (AGT) is a precursor of the RAS, and the inhibition of AGT may have significant cardiovascular benefits. But until now, there have been no reports of small molecule drugs targeting AGT. In this study, we designed a promoter-luciferase based system to screen for novel AGT inhibitors to alleviate SIMD. As a result of high-throughput screening, a total of 5 compounds from 351 medicinal herb-derived natural compounds were found inhibiting AGT. 18ß-glycyrrhetinic acid (18ßGA) was further identified as a potent suppressor of AGT. In vitro experiments, 18ßGA could inhibit the secretion of AGT by HepG2 cells and alleviate the elevated level of mitochondrial oxidative stress in cardiomyocytes co-cultured with HepG2 supernatants. In vivo, 18ßGA prolonged the survival rate of SIMD mice, enhanced cardiac function, and inhibited the damage of mitochondrial function and inflammation. In addition, the results showed that 18ßGA may reduce AGT transcription by downregulating hepatocyte nuclear factor 4 (HNF4) and that further alleviated SIMD. In conclusion, we provided a more efficient screening strategy for AGT inhibitors and expanded the novel role of 18ßGA as a promising lead compound in rescuing cardiovascular disease associated with RAS overactivation.

Gender Disparities in Patients' Decisions about the Management of Myocardial Infarction in East Chinese Province.

Background: Previous studies showed that there are gender disparities in various respects of acute myocardial infarction (AMI), including risk factors, symptoms, and outcomes. However, few of them noticed the gender disparities in patients' decision about the management of AMI, which might also be associated with the outcome. Aims: To identify gender disparities in patients' decisions about the management of myocardial infarction. Methods: In this cohort study, the critical time points including the time of symptom onset, visiting hospital, diagnosis of AMI, consent to coronary angiography (CAG), beginning of CAG, and balloon dilation were recorded. Medication and major adverse cardiac event (MACE) within 6 months were also recorded. Results: Female patients took more time from symptom onset to visiting hospital (P = 0.001), from diagnosis of AMI to consent to CAG (P < 0.05), and from door to needle/balloon than male (P < 0.05). Less female patients accepted CAG (P < 0.05) and coronary intervention/bypass grafting (P < 0.05). Less female patients kept good inherence to antiplatelet therapy (P < 0.05) and statins (P < 0.05) than male, more female preferred traditional Chinese medicine (TCM) than male patient (P < 0.05), and most of them had MACE within 6 months (P < 0.05). Patients' good adherence to antiplatelet therapy and statins and accepting coronary intervention/bypass grafting were associated with a reduced risk of MACE. Conclusion: Female patients were more reluctant to make decisions about emergency management of AMI and tended to choose conservative treatment. More female patients preferred TCM than evidence-based medicine. Their reluctance about the critical management of AMI and poor adherence to evidence-based medicine were associated with an elevated risk of MACE.

Chinese red yeast rice attenuates the development of angiotensin II-induced abdominal aortic aneurysm and atherosclerosis.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a chronic vascular disease characterized by medial degradation and inflammation. No medical approaches have been validated for treating AAA, and therapeutic options are limited to regular surveillance leading to surgical intervention. This study aimed to investigate whether administration of Chinese red yeast rice (Monascus purpureus; RYR) suppressed angiotensin II (AngII)-induced AAA and atherosclerosis. METHODS AND RESULTS: Apolipoprotein E-deficient male mice fed a normal diet were administered either RYR extract (200 mg/kg/day) or vehicle by gavage for 1 week before initiating AngII infusion (1000 ng/kg/min) via subcutaneous osmotic pumps for 28 days. Red yeast rice extract administration significantly suppressed AngII-induced expansion of suprarenal diameter and area (P<.05). Furthermore, RYR extract significantly reduced atherosclerotic lesion areas in both the intima of aortic arches and cross sections of aortic roots (P<.05). These effects were associated with reductions of serum total cholesterol, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, matrix metalloproteinase (MMP) 2 and increases of serum macrophage migration inhibitory factor, but no changes in serum interleukin (IL) 1α, IL-6, monocyte chemoattractant protein 1, MMP-9 and expression of MMP-2 and MMP-9 in aortic walls. CONCLUSIONS: This study demonstrated that RYR extract administration suppressed AngII-induced AAA and atherosclerosis associated with regulating inflammation responses independent of lipid-lowering effects. Red yeast rice may have preventive potential for patients with AAA.