Background Metabolic syndrome is characterized by insulin resistance, which impairs intracellular signaling pathways and endothelial NO bioactivity, leading to cardiovascular complications. Extracellular signal‐regulated kinase (ERK) is a major component of insulin signaling cascades that can be activated by many vasoactive peptides, hormones, and cytokines that are elevated in metabolic syndrome. The aim of this study was to clarify the role of endothelial ERK2 in vivo on NO bioactivity and insulin resistance in a mouse model of metabolic syndrome. Methods and Results Control and endothelial‐specific ERK2 knockout mice were fed a high‐fat/high‐sucrose diet (HFHSD) for 24 weeks. Systolic blood pressure, endothelial function, and glucose metabolism were investigated. Systolic blood pressure was lowered with increased NO products and decreased thromboxane A2/prostanoid (TP) products in HFHSD‐fed ERK2 knockout mice, and Nω‐nitro‐l‐arginine methyl ester (L‐NAME) increased it to the levels observed in HFHSD‐fed controls. Acetylcholine‐induced relaxation of aortic rings was increased, and aortic superoxide level was lowered in HFHSD‐fed ERK2 knockout mice. S18886, an antagonist of the TP receptor, improved endothelial function and decreased superoxide level only in the rings from HFHSD‐fed controls. Glucose intolerance and the impaired insulin sensitivity were blunted in HFHSD‐fed ERK2 knockout mice without changes in body weight. In vivo, S18886 improved endothelial dysfunction, systolic blood pressure, fasting serum glucose and insulin levels, and suppressed nonalcoholic fatty liver disease scores only in HFHSD‐fed controls. Conclusions Endothelial ERK2 increased superoxide level and decreased NO bioactivity, resulting in the deterioration of endothelial function, insulin resistance, and steatohepatitis, which were improved by a TP receptor antagonist, in a mouse model of metabolic syndrome.
We previously demonstrated the marked hepatosteatosis and endothelial dysfunction in hepatocyte-specific ERK2 knockout mice (LE2KO) with a high-fat/high-sucrose diet (HFHSD), but detailed metabolic changes and the characteristics in insulin-sensitive organs were not tested. This study aimed to characterize metabolic remodeling with changes in insulin-sensitive organs, which could induce endothelial dysfunction in HFHSD-LE2KO. The serum glucose and fatty acid (FA) were modestly higher in HFHSD-LE2KO than HFHSD-Control. FA synthesis genes were up-regulated, which was associated with the decreased phosphorylation of AMPK and ACC, and with the up-regulation of SREBP-1 in the liver from HFHSD-LE2KO. In FA and amino acids fraction analysis, arachidonic acid/eicosapentaenoic acid ratio, L-ornithine/arginine ratio, asymmetric dimethylarginine and homocysteine levels were elevated in HFHSD-LE2KO. Insulin-induced phosphorylation of AKT was blunted in skeletal muscle. Serum leptin and IL-1β were elevated, and serum adiponectin was decreased with the enlargement of epididymal adipocytes. Finally, the enhanced superoxide levels in the aorta, which were blunted with CCCP, apocynin, and tempol, were observed in HFHSD-LE2KO. A pre-incubation of aortic rings with tempol improved endothelial dysfunction in HFHSD-LE2KO. HFHSD-LE2KO revealed an acceleration of FA synthesis in the liver leading to insulin resistance in skeletal muscle and the enlargement of visceral adipocytes. Global metabolic remodeling such as changes in arginine metabolism, ω3/ω6 ratio, and adipocytokines, could affect the vascular oxidative stress and endothelial dysfunction in HFHSD-LE2KO.
Background 17α-hydroxylase deficiency (17OHD) is a rare autosomal recessive disorder. Aldosterone levels are usually low in patients with 17OHD. However, among the approximately 150 cases of 17OHD reported to date, aldosterone levels were not low in all cases. Therefore, some 17OHD cases may have been misdiagnosed as primary aldosteronism (PA) cases. Often before puberty, 17OHD is diagnosed because of abnormal genital morphology and menstrual irregularities. However, we report a very rare case of 17OHD in an elderly patient with a high aldosterone/renin ratio (ARR) similar to that in PA. Case presentation A 63-year-old Japanese woman was transferred to our medical facility for the evaluation of bilateral adrenal hypertrophy, which was incidentally discovered during an abdominal examination after cholecystectomy. The patient had hypokalemia and a high aldosterone/renin ratio. Her medical history included hypertension and right intracerebral capsular hemorrhage at the age of 30 years. Additional testing revealed low cortisol, high adrenocorticotropic hormone, and low testosterone and dehydroepiandrosterone sulfate, indicating congenital adrenal hyperplasia. Genetic analysis revealed a mutation in the CYP17A1 gene and a karyotype of 46, XY; hence, she was diagnosed with 17OHD. Conclusion 17OHD can resemble PA. The combination of a high ARR and low cortisol level should trigger the consideration of 17OHD.
Aims:The long-term prognostic value of the bioavailability of l-arginine, an important source of nitric oxide for the maintenance of vascular endothelial function, has not been investigated fully. We therefore investigated the relationship between amino acid profile and long-term prognosis in patients with a history of standby coronary angiography. Methods:We measured the serum concentrations of l-arginine, l-citrulline, and l-ornithine by high-speed liquid chromatography. We examined the relationship between the l-arginine/l-ornithine ratio and the incidence of all-cause death, cardiovascular death, and major adverse cardiovascular events (MACEs) in 262 patients (202 men and 60 women, age 65±13 years) who underwent coronary angiography over a period of ≤ 10 years.Results: During the observation period of 5.5±3.2 years, 31 (12%) patients died, including 20 (8%) of cardiovascular death, while 32 (12%) had MACEs. Cox regression analysis revealed that l-arginine/l-ornithine ratio was associated with an increased risk for all-cause death (unadjusted hazard ratio, 95% confidence interval) (0.940, 0.888-0.995) and cardiovascular death (0.895, 0.821-0.965) (p<0.05 for all). In a mod el adjusted for age, sex, hypertension, hyperlipidemia, diabetes, current smoking, renal function, and log10-transformed brain natriuretic peptide level, cardiovascular death (0.911, 0.839-0.990, p=0.028) retained an association with a low l-arginine/ l-ornithine ratio. When the patients were grouped according to an l-arginine/l-ornithine ratio of 1.16, the lower l-arginine/l-ornithine ratio group had significantly higher incidence of all-cause death, cardiovascular death, and MACEs. Conclusion:A low l-arginine/l-ornithine ratio may be associated with increased 10-year cardiac mortality.
Metabolic syndrome (Mets) is the major contributor to the onset of metabolic complications, such as hypertension, type 2 diabetes mellitus (DM), dyslipidemia, and non-alcoholic fatty liver disease, resulting in cardiovascular diseases. C57BL/6 mice on a high-fat and high-sucrose diet (HFHSD) are a well-established model of Mets but have minor endothelial dysfunction in isolated aortas without perivascular adipose tissue (PVAT). The purpose of this study was to evaluate the effects of additional factors such as DM, dyslipidemia, and steatohepatitis on endothelial dysfunction in aortas without PVAT. Here, we employed eight-week-old male C57BL/6 mice fed with a normal diet (ND), HFHSD, steatohepatitis choline-deficient HFHSD (HFHSD-SH), and HFHSD containing 1% cholesterol and 0.1% deoxycholic acid (HFHSD-Chol) for 16 weeks. At week 20, some HFHSD-fed mice were treated with streptozocin to develop diabetes (HFHSD-DM). In PVAT-free aortas, the endothelial-dependent relaxation (EDR) did not differ between ND and HFHSD (p = 0.25), but in aortas with PVAT, the EDR of HFHSD-fed mice was impaired compared with ND-fed mice (p = 0.005). HFHSD-DM, HFHSD-SH, and HFHSD-Chol impaired the EDR in aortas without PVAT (p < 0.001, p = 0.019, and p = 0.009 vs. ND, respectively). Furthermore, tempol rescued the EDR in those models. In the Mets model, the EDR is compromised by PVAT, but with the addition of DM, dyslipidemia, and SH, the vessels themselves may result in impaired EDR.
Background: Extracellular signal-regulated kinases 1/2 (ERK1/2) play significant roles in proliferation, migration, and cell death. Tyrosine kinase inhibitors (TKIs) have a serious concern for cardiotoxicity and these agents target to EGFR/Ras/Raf/MEK/ERK pathway. In previous reports, SM22α-Cre drived EGFR receptor knockout mice revealed cardiac dysfunction. Hypothesis: We hypothesized if SM22α-Cre drived ERK2 contributed to the cardiac dysfunction mimicking toxicity of TKIs. Methods & Results: We generated SM22α-drived ERK2 knockout mice (SM22α-EKO) by crossing SM22α-Cre mice and ERK2-flox mice. The protein expressions of ERK2 in aorta and heart were markedly lowered in SM22α-EKO, whereas similar in brain, kidney, liver, spleen, and bone marrow. SM22α-EKO displayed lower exercise tolerance and peak oxygen consumptions. Echocardiography revealed left ventricular thickness and dilatation with decreased % fraction shortening (21±4 vs. 38±2%, p=0.0002). Pathological study showed that heart weight was twice accompanied by increases in cardiomyocyte volume, stronger cardiac fibrosis, and inflammations (Figure 1). Western blot analysis showed that the phosphorylation of Akt, p-38 MAP kinase, and STAT3 were also up-regulated in SM22α-EKO with control. Phenylephrine - induced vascular contraction was increased and acetylcholine - induced relaxation was impaired in SM22α-EKO. Finally, SM22α-EKO significantly reduced life span in the Kaplan-Meier plot (Figure 2). Conclusion: SM22α-EKO mice revealed spontaneous cardiac dysfunction with the activation of multiple signaling cascades for hypertrophy and inflammation resulting in sudden death. Deletion of ERK2 in heart and smooth muscle cells also led to hypercontraction of phenylephrine / endothelial dysfunction and perivascular cardiac fibrosis and inflammation. SM22α-EKO might be a valuable model for TKI - induced cardiotoxicity.
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