No abstract

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.

Heart failure (HF) is a syndrome with global clinical and socioeconomic burden worldwide owing to its poor prognosis. Accumulating evidence has implicated the possible contribution of gut microbiota-derived metabolites, short-chain fatty acids (SCFAs), on the pathology of a variety of diseases. The changes of SCFA concentration were reported to be observed in various cardiovascular diseases including HF in experimental animals and humans. HF causes hypoperfusion and/or congestion in the gut, which may lead to lowered production of SCFAs, possibly through the pathological changes of the gut microenvironment including microbiota composition. Recent studies suggest that SCFAs may play a significant role in the pathology of HF, possibly through an agonistic effect on G-protein-coupled receptors, histone deacetylases (HDACs) inhibition, restoration of mitochondrial function, amelioration of cardiac inflammatory response, its utilization as an energy source, and remote effect attributable to a protective effect on the other organs. Collectively, in the pathology of HF, SCFAs might play a significant role as a key mediator in the gut–heart axis. However, these possible mechanisms have not been entirely clarified and need further investigation.

No abstract

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.

The optimal heart rate (HR) in patients with heart failure with reduced ejection fraction (HFrEF) has been ill-defined. Recently, a formula was proposed for estimating the target heart rate (THR), which eliminates the overlap between the E and A wave (E-A overlap). We aim to validate its prognostic significance in the multicenter WET-HF registry. This study used data from 647 patients with HFrEF hospitalized for acute decompensated HF (ADHF). The patients were divided into the 2 groups by THR. The primary endpoint was defined as the composite of all-cause death and ADHF readmission. The THR successfully discriminated the incidence of the primary endpoint, whereas no significant difference was observed in the primary endpoint when dividing the patients by uniform cutoff 70 bpm. HR at discharge ≤ THR was inversely associated with the primary endpoint. Restricted cubic spline analysis demonstrated the difference between HR at discharge, and THR (ΔHR) from −10 to ±0 was associated with a lower risk of primary endpoint and ΔHR from ±0 to +15 was associated with a higher risk. THR discriminated long-term outcomes in patients with HFrEF more efficiently than the uniform cutoff, suggesting that it may aid in tailored HR reduction strategies.

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.

Introduction: Right ventricular (RV) dysfunction is the strongest predictor of mortality in pulmonary artery hypertension (PAH). Reactive oxygen species in heart failure cause irreversible oxidation of sarcoplasmic reticulum (SR) Ca 2+ -ATPase2 (SERCA2) C674, which results in SERCA2 dysfunction and intracellular Ca 2+ overload. However, the contribution of the loss of the thiol on C674 SERCA2 and RV failure in PAH remains unclear. Hypothesis: The loss of the thiol on C674 SERCA2 contributes to the RV dysfunction in PAH. Methods & Results: We employed the SERCA2 C674S heterozygote knock-in (SKI) mice, in which C674 is replaced by serine, mimics oxidative modification of SERCA2 by loss of the specific thiol. Wild-type mice (WT) and SKI were exposed to either normoxia (Nx) or chronic hypoxia (Hx) for four weeks. Hypoxia elevated RV systolic pressure (WT-Nx: 21.4mmHg vs. WT-Hx: 37.0mmHg, P<0.0001) and represented pulmonary vascular remodeling similarly both in WT and SKI. In histology, SKI-Hx showed the markedly increased Fulton's Index with higher levels of the mRNA expression of atrial natriuretic peptide and B-type natriuretic peptide than WT-Hx. In the exercise test, exercise duration was shorter and peak oxygen consumption was decreased in SKI-Hx than WT Hx. The mRNA levels of SERCA2 were not changed among the four groups. In Ca 2+ transient measurement of isolated myocytes with Fluo-4, SKI prolonged the time to 50% of cytosolic Ca 2+ extrusion (T50) and lower the peak Ca 2+ transient amplitude (F/F0) than WT under Nx. Prolonged T50 and lowered peak F/F0 were observed in WT-Hx, both of which additionally progressed in SKI-Hx. Conclusions: Hypoxia impaired SR Ca 2+ homeostasis in RV. SKI additionally impaired SR Ca 2+ homeostasis with the progression of RV hypertrophy. The loss of the thiol on C674 SERCA2 contributed to the pathogenesis of RV failure in PAH.