Tetsuya Seko

Activation of RhoA and Inhibition of Myosin Phosphatase as Important Components in Hypertension in Vascular Smooth Muscle

Abstract— Two mechanisms are proposed to account for the inhibition of myosin phosphatase (MP) involved in Ca2+ sensitization of vascular muscle, ie, phosphorylation of either MYPT1, a target subunit of MP or CPI-17, an inhibitory phosphoprotein. In cultured vascular aorta smooth muscle cells (VSMCs), stimulation with angiotensin II activated RhoA, and this was blocked by pretreatment with 8-bromo-cGMP. VSMCs stimulated by angiotensin II, endothelin-1, or U-46619 significantly increased the phosphorylation levels of both MYPT1 (at Thr696) and CPI-17 (at Thr38). The angiotensin II-induced phosphorylation of MYPT1 was completely blocked by 8-bromo-cGMP or Y-27632 (a Rho-kinase inhibitor), but not by GF109203X (a PKC inhibitor). In contrast, phosphorylation of CPI-17 was inhibited only by GF109203X. Y-27632 dramatically corrected the hypertension in N&ohgr;-nitro-l-arginine methyl ester (L-NAME)-treated rats, and this hypertension also was sensitive to isosorbide mononitrate. The level of the active form of RhoA was significantly higher in aortas from L-NAME-treated rats. Expression of RhoA, Rho-kinase, MYPT1, CPI-17, and myosin light chain kinase were not significantly different in aortas from L-NAME-treated and control rats. Activation of RhoA without changes in levels of other signaling molecules were observed in three other rat models of hypertension, ie, stroke-prone spontaneously hypertensive rats, renal hypertensive rats, and DOCA-salt rats. These results suggest that independent of the cause of hypertension, a common point in downstream signaling and a critical component of hypertension is activation of RhoA and subsequent activation of Rho-kinase.

Phosphorylation of CPI-17, an inhibitory phosphoprotein of smooth muscle myosin phosphatase, by Rho-kinase

Phosphorylation of CPI‐17 by Rho‐associated kinase (Rho‐kinase) and its effect on myosin phosphatase (MP) activity were investigated. CPI‐17 was phosphorylated by Rho‐kinase to 0.92 mol of P/mol of CPI‐17 in vitro. The inhibitory phosphorylation site was Thr38 (as reported previously) and was identified using a point mutant of CPI‐17 and a phosphorylation state‐specific antibody. Phosphorylation by Rho‐kinase dramatically increased the inhibitory effect of CPI‐17 on MP activity. Thus, CPI‐17 as a substrate of Rho‐kinase could be involved in the Ca2+ sensitization of smooth muscle contraction as a downstream effector of Rho‐kinase.

A case of primary cardiac lymphoma located in the pericardial effusion

Primary cardiac lymphoma is a rare disorder with a poor prognosis. We present here a case of 77-year-old woman who was diagnosed as having cardiac lymphoma antemortem according to a cytologic examination of the pericardial effusion. Determination of the levels of serum-soluble interleukin-2 receptor and serum deoxythymidine kinase was useful for the diagnosis. Echocardiography, computed tomography, magnetic resonance imaging, and gallium scan revealed neither lymphadenopathy nor tumor in the heart, so she was diagnosed as having malignant lymphoma that probably originated from the pericardium. Systemic chemotherapy with CHOP (cyclophosphamide, farmorubicin, oncovin, and prednisolone) resulted in a complete resolution of the pericardial effusion. She has been in remission 48 months after discontinuation of the chemotherapy.

MPS 04-07 SHORT AND MID-TERM OUTCOMES OF ACUTE MYOCARDIAL INFARCTION WITH ELEVATED SYSTOLIC BLOOD PRESSURE ON ADMISSION

Objective: Although lower admission systolic blood pressure (SBP) has been established as a poor prognostic factor in patients with acute myocardial infarction (AMI), the impact of preserved admission SBP on short and mid-term outcomes has not been fully evaluated. Design and Method: From January 2013 to March 2015, 1281 consecutive patients with AMI were registered in Mie ACS Registry, a prospective, multicenter registry in Japan. We evaluated 1122 patients (mean age 68 ± 13 years, male 78%) except for 159 patients with admission SBP < 100 mmHg. Patients were divided into three groups according to admission SBP: 100–139 mmHg (normal admission SBP; NBP group, n = 612), 140–179 mmHg (moderately elevated admission SBP; MBP group, n = 419) and ≥180 mmHg (excessively elevated admission SBP; EBP group, n = 91). The clinical characteristics, 30-day and 1-yaer outcomes (follow-up rate 94.7%) were compared among the three groups. Results: The rate of primary percutaneous coronary intervention and the number of diseased coronary vessels were not significantly different among the three groups. The Killip classification and the peak creatine kinase values were lowest in the MBP group. Heart failure, arrhythmia, shock and multi-organ failure during hospitalization were most often in the NBP group, but myocardial rupture was no significant difference in the three groups. The 30-day cumulative mortality was trend to be high in the NBP group (6.5%, 3.3% and 4.4% for NBP, MBP and EBP group, respectively, Log-Rank P = 0.069), and 1-year cumulative mortality after hospital discharge was significantly high in NBP group (5.5%, 1.6% and 2.4% for NBP, MBP and EBP group, respectively, Log-Rank P = 0.007) than other two groups (Figure). Conclusions: Admission SBP of less than 140 mmHg can be a risk of hemodynamic instability during hospitalization and an indicator of poor outcomes after hospital discharge in patients with AMI and preserved admission SBP.

Left Ventricular Diastolic Dysfunction and Exercise Intolerance in Type 2 Diabetes Patients with Endothelial Dysfunction

Introduction: Endothelial dysfunction plays a central role in the pathogenesis of diabetic vascular disease. Hypothesis: Although resultant left ventricular diastolic dysfunction is hypothesized to reduce exercise capacity, limited data exist on the relation between endothelial function, left ventricular diastolic function and exercise capacity in patients with type 2 diabetes. Methods: We recruited 231 subjects with type 2 diabetes, a preserved ejection fraction, a negative stress test and a sodium-restricted diet. All subjects underwent a brachial artery flow-mediated dilation (FMD) measurement, a transthoracic echocardiography and a standard submaximal Bruce protocol treadmill exercise test during the hospitalization period for diabetes education program. Results: Impaired FMD (%FMD 8) were found in 193 subjects (84%) and 174 subjects (75%), respectively, of which 11 (5%) had diastolic dysfunction (E/E’ >15). Mean E/E’ by quartile (Q) were: Q1 6.9, Q2 8.9, Q3 10.4, and Q4 14.0. E/E’ was inversely correlated with %FMD (2.9 ± 4.3%, r = -0.19, p = 0.003) and exercise duration (460 ± 150 sec, r = -0.30, p <0.001). Compared with subjects in Q4, those in Q1, Q2 and Q3 had longer exercise duration (Q1 500 ± 150 sec, Q2 510 ± 140 sec, Q3 460 ± 140 sec and Q4 390 ± 140 sec, p <0.001). After adjustment for potential confounders including age, gender, smoking, body mass index, medication for hypertension, diabetes duration of more than 5 years, HbA1c and systolic blood pressure, %FMD and exercise duration were significantly associated with E/E’ (β = -0.17 and -0.18, p = 0.006 and 0.014) in all subjects. Conclusions: Diabetes patients with impaired endothelial function have impaired left ventricular diastolic function potentially leading to exercise intolerance. ![][1] [1]: /embed/graphic-1.gif

Intra-aortic balloon pump induced dynamic left ventricular outflow tract obstruction and cardiogenic shock after very late stent thrombosis in the left anterior descending coronary artery

An 81-year-old woman had undergone percutaneus coronary intervention to mid left anterior descending coronary artery with a drug-eluting stent for effort angina pectoris. Although she had remained asymptomatic for 3 years, she developed cardiogenic shock following acute myocardial infarction due to stent thrombosis. Her condition deteriorated despite successful revascularization and an initiation of intra-aortic balloon pump (IABP). Transthoracic echocardiography examination revealed systolic anterior motion of the anterior mitral leaflet which caused severe left ventricular outflow tract obstruction (LVOTO) and moderate mitral regurgitation. Discontinuation of IABP resulted in immediate and complete recovery from cardiogenic shock and echocardiography revealed no LVOTO. These findings may shed new light on the underlying mechanism responsible for deteriorating LVOTO and yield new insights into the assessment and the treatment of cardiogenic shock with dynamic LVOTO.