The angiotensin II type 1 (AT 1 ) receptor is a G protein-coupled receptor that has a crucial role in the development of load-induced cardiac hypertrophy. Here, we show that cell stretch leads to activation of the AT 1 receptor, which undergoes an anticlockwise rotation and a shift of transmembrane (TM) 7 into the ligandbinding pocket. As an inverse agonist, candesartan suppressed the stretch-induced helical movement of TM7 through the bindings of the carboxyl group of candesartan to the specific residues of the receptor. A molecular model proposes that the tight binding of candesartan to the AT 1 receptor stabilizes the receptor in the inactive conformation, preventing its shift to the active conformation. Our results show that the AT 1 receptor undergoes a conformational switch that couples mechanical stress-induced activation and inverse agonist-induced inactivation.

Vascular endothelial (VE)-cadherin is a cell-cell adhesion molecule involved in endothelial barrier function. Here, we show that initial circumferential actin bundling induced by cyclic AMP-Epac-Rap1 signal and its linkage to VE-cadherin through α- and β-catenins lead to the stabilization of VE-cadherin at cell-cell contacts.

Abstract-Rho-kinase, an effector of Rho GTPase, increases the contractility of vascular smooth muscle by phosphorylating myosin light chain (MLC) and by inactivating MLC phosphatase. A wide variety of extracellular stimuli activate RhoA via G protein-coupled receptors. In the present study, we demonstrate a novel cell-cell interaction-mediated Rho activation signaling pathway in vascular smooth muscle cells (VSMCs). Among many receptor tyrosine kinases, the Eph family receptors are unique in that they require cell-cell interaction to engage their ligands, ephrin. We found that a novel VSMC-specific guanine nucleotide exchange factor (GEF) for Rho (Vsm-RhoGEF/KIAA0915) was expressed specifically in VSMCs of several organs including the heart, aorta, liver, kidney, and spleen, as examined by the immunohistochemical analysis using a specific antibody against Vsm-RhoGEF. Based on the association of Vsm-RhoGEF with EphA4 in quiescent cells, we tested whether EphA4 and Vsm-RhoGEF were expressed in the same tissue and further studied the molecular mechanism of Vsm-RhoGEF regulation by EphA4. Immunohistochemical analysis showed that EphA4 and Vsm-RhoGEF expression overlapped in VSMCs. Additionally, tyrosine phosphorylation of Vsm-RhoGEF induced by EphA4 upon ephrin-A1 stimulation enhanced the Vsm-RhoGEF activity for RhoA. The requirement of Vsm-RhoGEF for ephrin-A1-induced assembly of actin stress fibers in VSMCs was shown by the overexpression of a dominant-negative form of VSM-RhoGEF and by the depletion of Vsm-RhoGEF using RNA interference. These results suggested that ephrin-A1-triggered EphA4-Vsm-RhoGEF-RhoA pathway is involved in the cell-cell interaction-mediated RhoA activation that regulates vascular smooth muscle contractility. Key Words: smooth muscle cells Ⅲ Rho Ⅲ Eph Ⅲ ephrin Ⅲ contraction V ascular smooth muscle cell (VSMC) contractility regulates vascular tone to maintain blood circulation. Increased vascular smooth muscle contraction results in spasm and chronic contraction leads to hypertension, both of which contribute to cardiovascular pathology. Vascular contraction is regulated by actin-myosin II coupling in a Ca 2ϩ -dependent manner and a Ca 2ϩ -independent manner. The Rho GTPases play an important role in the Ca 2ϩ -independent vascular contraction, known as Ca 2ϩ sensitization. 1 Myosin II is regulated by phosphorylation and dephosphorylation of the myosin regulatory light chain. The former is controlled by myosin light chain (MLC) kinase regulated by Ca 2ϩ /calmodulin, and the latter is regulated by MLC phosphatase (MLCP). Recently, RhoA has been shown to be involved in the inhibition of MLCP via the Rho effector molecule, Rho-kinase. The phosphorylation of MLCP inhibits the phosphatase activity and thereby activates MLC, 2 resulting in contraction of smooth muscle. In addition to MLCP phosphorylation, Rho-kinase directly phosphorylates MLC and increases the contractility of myosin II. 3 These data support that Rho activation is clinically involved in vasospastic angina and unfavorable smooth mu...

Landiolol and bisoprolol prevented postoperative AF. The anti-ischemic, anti-inflammatory, and anti-oxidant effects of these beta-blockers presumably inhibited the onset of AF.

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BackgroundAlthough clinical trials have proved that statin can be used prophylactically against cardiovascular events, the direct effects of statin on plaque development are not well understood. We generated low‐density lipoprotein receptor knockout (LDLR −/−) pigs to study the effects of early statin administration on development of atherosclerotic plaques, especially advanced plaques.Methods and Results LDLR −/− pigs were generated by targeted deletion of exon 4 of the LDLR gene. Given a standard chow diet, LDLR −/− pigs showed atherosclerotic lesions starting at 6 months of age. When 3‐month‐old LDLR −/− pigs were fed a high‐cholesterol, high‐fat (HCHF) diet for 4 months (HCHF group), human‐like advanced coronary plaques developed. We also fed 3‐month‐old LDLR −/− pigs an HCHF diet with pitavastatin for 4 months (Statin Prophylaxis Group). Although serum cholesterol concentrations did not differ significantly between the 2 groups, intravascular ultrasound revealed 52% reduced plaque volume in statin‐treated pigs. Pathological examination revealed most lesions (87%) in the statin prophylaxis group were early‐stage lesions, versus 45% in the HCHF diet group (P<0.01). Thin‐cap fibroatheroma characterized 40% of the plaques in the HCHF diet group versus 8% in the statin prophylaxis group (P<0.01), intraplaque hemorrhage characterized 11% versus 1% (P<0.01), and calcification characterized 22% versus 1% (P<0.01).ConclusionsResults of our large animal experiment support statin prophylaxis before the occurrence of atherosclerosis. Early statin treatment appears to retard development of coronary artery atherosclerosis and ensure lesion stability. In addition, the LDLR −/− pigs we developed represent a large animal model of human‐like advanced coronary plaque suitable for translational research.

SummaryBrugada syndrome is an inherited disorder that predisposes some patients to sudden cardiac death. It is not well established which Brugada syndrome patients are at risk of life-threatening arrhythmias. We investigated whether standard 12-lead electrocardiograms (ECG) can identify such patients. The subjects were 35 men with Brugada syndrome (mean age, 50.1 ± 12.4 years). Documented ventricular fibrillation or aborted sudden cardiac arrests were judged to be related to the Brugada syndrome. Ten patients (mean age, 49.6 ± 14.9 years) were symptomatic, and 25 (mean age, 50.3 ± 11.5 years) were asymptomatic. We determined the PR interval, QRS duration, and QT interval from baseline 12-lead ECG leads II and V2 as well as the J point elevation amplitude of lead V2. The QRS interval was measured from QRS onset to the J point in leads II and V2. The only significant difference between the symptomatic and asymptomatic patients was the QRS duration measured from lead V2. The mean QRS interval was 129.0 ± 23.9 ms in symptomatic patients versus 108.3 ± 15.9 ms in asymptomatic patients (P = 0.012). A QRS interval in lead V2 ≥ 120 ms was found to be a possible predictor of a life-threatening ventricular arrhythmia and/or syncope (P = 0.012). Prolonged QRS duration as measured on a standard 12-lead ECG is associated with ventricular arrhythmia and could serve as a simple noninvasive marker of vulnerability to life-threatening cardiac events in patients with Brugada syndrome. (Int Heart J 2011; 52: 98-102) Key words: Brugada syndrome, Sudden death, Ventricular fibrillation, QRS width B rugada syndrome, which was introduced as a clinical entity in 1992, is a genetic disorder that increases the risk of sudden death secondary to ventricular tachycardia/fibrillation (VT/VF) in patients with structurally normal hearts.1,2) The syndrome is estimated to be responsible for 4% of all sudden deaths and at least 20% of sudden deaths in patients with structurally normal hearts.3) Inheritance of Brugada syndrome occurs via an autosomal dominant mode of transmission with variable penetrance involving several genes. SC-N5A, which codes subunit I Na of sodium channel α, is mutated in 20%-30% of Brugada syndrome patients. 4,5) Mutations in the GPD1L gene 6) and the CACNA1 and CACNB2 genes 7) have also been identified, but these gene variations are infrequent. The typical ST segment elevation in the precordial leads that characterizes Brugada syndrome electrocardiographically can be transitory, vary over time, or be modified by various factors such as vagal tonus, body temperature, and medications. 8,9) This elevation can have a saddleback appearance with a J wave amplitude of ≥ 2 mm and an elevation in the terminal portion of the ST segment of ≥ 1 mm, and then either a positive or biphasic T wave (type 2 electrocardiogram [ECG]) or can be characterized by either a saddleback or coved appearance with an ST segment elevation of < 1 mm (type 3 ECG).10)The vulnerability of individuals with the "Brugada sign" to sudden cardiac death or a life...