Jin Oshikawa

Identification of an increased short-term blood pressure variability on ambulatory blood pressure monitoring as a coronary risk factor in diabetic hypertensives.

We examined risk factors for coronary heart disease (CHD) by ambulatory blood pressure (BP) monitoring in 72 diabetic hypertensives who were hospitalized for the educational program. The patients were divided into two groups (CHD group, 19 subjects; and non-CHD group, 53 subjects) along with or without co-existing CHD. On ambulatory BP monitoring, no significant differences were found between the groups regarding BP values through the day. However, the CHD group had a significantly grater BP variability than non-CHD group. The result of logistic regression analysis demonstrated that nighttime systolic BP variability was an independent risk factor for CHD.

Caveolin gene transfer improves glucose metabolism in diabetic mice

Caveolin, a member of the membrane-anchoring protein family, accumulates various growth receptors in caveolae and inhibits their function. Upregulation of caveolin attenuates cellular proliferation and growth. However, the role of caveolin in regulating insulin signals remains controversial. Here, we demonstrate that caveolin potently enhances insulin receptor (IR) signaling when overexpressed in the liver in vivo. Adenovirus-mediated gene transfer was used to overexpress caveolin specifically in the liver of diabetic obese mice, which were generated with a high-fat diet. Expression of molecules involved in IR signaling, such as IR or Akt, remained unchanged after gene transfer. However, hepatic glycogen synthesis was markedly increased with a decrease in phosphoenolpyruvate carboxykinase protein expression. Insulin sensitivity was increased after caveolin gene transfer as determined by decreased blood glucose levels in response to insulin injection and fasting blood glucose levels. Glucose tolerant test performance was also improved. Similar improvements were obtained in KKA(y) genetically diabetic mice. Adenovirus-mediated overexpression of caveolin-3 in hepatic cells also enhanced IR signaling, as shown by increased phosphorylation of IR in response to insulin stimulation and higher glycogen synthesis at baseline. These effects were attributed mostly to increased insulin receptor activity and caveolin-mediated, direct inhibition of protein tyrosine phosphatase 1B, which was increased in obese mouse livers. In conclusion, our results suggest that caveolin is an important regulator of glucose metabolism that can enhance insulin signals.

Effects of aliskiren-based therapy on ambulatory blood pressure profile, central hemodynamics, and arterial stiffness in nondiabetic mild to moderate hypertensive patients.

J Clin Hypertens (Greenwich). 2012;00:000–000. ©2012 Wiley Periodicals, Inc.

Effects of the oriental herbal medicine Bofu-tsusho-san in obesity hypertension: A multicenter, randomized, parallel-group controlled trial (ATH-D-14-01021.R2)

OBJECTIVE There is no clinical evidence that supports the benefit of integrative medicine, defined as combination therapy of oriental and western medicine, on obesity-related hypertension. This study evaluates the efficacy of Bofu-tsusho-san (BOF), an oriental herbal medicine, on the ambulatory blood pressure (BP) profile in hypertensive patients with obesity. METHODS The study design was a multicenter, randomized, open-label, parallel-group controlled trial in 107 hypertensive patients with obesity. Participants were randomly assigned to receive either the conventional control therapy or BOF add-on therapy. In both groups antihypertensive therapy was aimed at achieving the target clinic BP. The primary outcome was change in the ambulatory BP profile from baseline to 24 weeks after randomization. RESULTS Daytime systolic BP variability, an important parameter of ambulatory BP profile, was decreased in the BOF group, and the difference in the changes in daytime systolic BP variability was significant between the BOF and control group (Control vs BOF; the change from baseline in daytime systolic BP variability, 1.0±3.3 vs -1.0±3.3%; p=0.006). CONCLUSION The BOF add-on therapy effectively improved the ambulatory BP variability. This is the first report suggesting that an integrative medicine approach may exert favorable effects on obesity-related hypertension compared with conventional pharmaceutical treatment. CLINICAL TRIAL REGISTRATION UMIN000003878.

Caveolin-3 inhibits growth signal in cardiac myoblasts in a Ca2+-dependent manner.

Caveolin, a major protein component of caveolae, directly interacts with multiple signaling molecules, such as Ras and growth factor receptors, and inhibits their function. However, the role of the second messenger system in mediating this inhibition by caveolin remains poorly understood. We examined the role of Ca2+ ‐dependent signal in caveloin‐mediated growth inhibition using a rat cardiac myoblast cell line (H9C2), in which the expression of caveolin‐3, the muscle specific subtype, can be induced using the LacSwitch system. Upon induction with IPTG and serum‐starvation, the expression of caveolin‐3 was increased by 3.3‐fold relative to that of mock‐induced cells. The recombinant caveolin‐3 was localized to the same subcellular fraction as endogenous caveolin‐3 after sucrose gradient purification. Angiotensin II enhanced ERK phosphorylation, but this enhancement was significantly decreased in caveolin‐3‐induced cells in comparison to that in mock‐induced cells. Similarly, when cells were stimulated with fetal calf serum, DNA synthesis, as determined by [3H]‐thymidine incorporation, was significantly decreased in caveolin‐3‐induced cells. When cells were treated with Ca2+ chelator (BAPTA and EGTA), however, this attenuation was blunted. Calphostin (PKC inhibitor), but not cyclosporine A treatment (calcineurin inhibitor), blunted this attenuation in caveolin‐3 induced cells. Our findings suggest that caveolin exhibits growth inhibition in a Ca2+‐dependent manner, most likely through PKC, in cardiac myoblasts.

Angiotensin receptor blocker (ARB)–diuretic versus ARB–calcium channel blocker combination therapy for hypertension uncontrolled by ARB monotherapy

Abstract Diuretics or calcium channel blockers (CCBs) are used concomitantly with an angiotensin II receptor blocker (ARB). However, it is not established which ARB-based combination therapy is the most effective and safe. This prospective randomized open-label study compared the efficacy and safety of a fixed-dose tablet of losartan (LST)–hydrochlorothiazide (HCTZ) (n = 99) and LST–amlodipine (AML) (n = 77) in Japanese patients whose hypertension was uncontrolled by ARB monotherapy. Blood pressure changed similarly over the 12-month study period. Only LST–HCTZ significantly increased serum uric acid (SUA) in patients with low baseline SUA (<5.6 mg/dL) but not in patients with high baseline SUA.

Behçet's disease complicated by IgA nephropathy with nephrotic syndrome.

A 65-year-old woman with a 48-year history of Behçet’s disease associated with nephrotic syndrome is described. Immunofluorescence study revealed IgA nephropathy. Following treatment with an angiotensin II type-I receptor-blocker, an anti-platelet drug, and an HMG-CoA reductase inhibitor, accompanied by dietary restrictions of protein and sodium, proteinuria was markedly decreased. This report describes our experience with a rare entity of Behçet’s disease complicated by nephrotic syndrome due to IgA nephropathy. Routine urine examination and renal biopsy are needed for the detection and diagnosis of renal problems with Behçet’s disease.