Sota Nakajima

Essential Role of Bone Marrow for Microvascular Endothelial and Metabolic Functions in Mice

Rationale: We have previously demonstrated that the importance of endothelium-derived hyperpolarizing factor (EDHF) increases as the vessel size decreases and that endothelium-derived hydrogen peroxide (H2O2) is an EDHF in animals and humans, for which endothelial nitric oxide synthase (eNOS) is the major source. Recent studies have suggested the important role of the bone marrow (BM) in modulating cardiovascular and metabolic functions. Objective: We aimed to examine whether BM plays a role in modulating microvascular endothelial and metabolic functions in mice, and if so, to elucidate the mechanisms involved. Methods and Results: Male eNOS−/− mice were transplanted with BM cells from wild-type (WT) or eNOS−/− mice and were maintained for 6 weeks. Endothelium-dependent relaxations and hyperpolarizations of mesenteric arteries to acetylcholine were reduced in eNOS−/− mice and were markedly improved when transplanted with WT-BM but not with eNOS−/−-BM. The enhanced component of endothelium-dependent relaxations was abolished by catalase, indicating that the improved responses were mediated by H2O2. In contrast, no such beneficial effect was noted in the aorta. Reduced plasma adiponectin levels and impaired glucose tolerance in eNOS−/− mice were also improved by WT-BM transplantation. Neuronal nitric oxide synthase (nNOS) in mesenteric arteries of eNOS−/− mice was significantly upregulated only when transplanted with WT-BM. Importantly, the beneficial effects of WT-BM transplantation were absent in eNOS−/−/adiponectin−/− or eNOS−/−/nNOS−/− mice. Conclusions: These results provide the first evidence that BM plays an important role in modulating microvascular endothelial and metabolic functions, for which adiponectin and nNOS may be involved.

Rho-Kinase Inhibition Ameliorates Metabolic Disorders through Activation of AMPK Pathway in Mice

Background Metabolic disorders, caused by excessive calorie intake and low physical activity, are important cardiovascular risk factors. Rho-kinase, an effector protein of the small GTP-binding protein RhoA, is an important cardiovascular therapeutic target and its activity is increased in patients with metabolic syndrome. We aimed to examine whether Rho-kinase inhibition improves high-fat diet (HFD)-induced metabolic disorders, and if so, to elucidate the involvement of AMP-activated kinase (AMPK), a key molecule of metabolic conditions. Methods and Results Mice were fed a high-fat diet, which induced metabolic phenotypes, such as obesity, hypercholesterolemia and glucose intolerance. These phenotypes are suppressed by treatment with selective Rho-kinase inhibitor, associated with increased whole body O2 consumption and AMPK activation in the skeletal muscle and liver. Moreover, Rho-kinase inhibition increased mRNA expression of the molecules linked to fatty acid oxidation, mitochondrial energy production and glucose metabolism, all of which are known as targets of AMPK in those tissues. In systemic overexpression of dominant-negative Rho-kinase mice, body weight, serum lipid levels and glucose metabolism were improved compared with littermate control mice. Furthermore, in AMPKα2-deficient mice, the beneficial effects of fasudil, a Rho-kinase inhibitor, on body weight, hypercholesterolemia, mRNA expression of the AMPK targets and increase of whole body O2 consumption were absent, whereas glucose metabolism was restored by fasudil to the level in wild-type mice. In cultured mouse myocytes, pharmacological and genetic inhibition of Rho-kinase increased AMPK activity through liver kinase b1 (LKB1), with up-regulation of its targets, which effects were abolished by an AMPK inhibitor, compound C. Conclusions These results indicate that Rho-kinase inhibition ameliorates metabolic disorders through activation of the LKB1/AMPK pathway, suggesting that Rho-kinase is also a novel therapeutic target of metabolic disorders.

Different postprandial lipid metabolism and insulin resistance between non-diabetic patients with and without coronary artery disease

BACKGROUND Postprandial hyperlipidemia and hyperinsulinemia have been thought to play an important role in the development of atherosclerosis. Diabetes mellitus (DM) has an impact on lipid metabolism, however, little is known about the relationship between the postprandial lipid and glucose metabolism in normoglycemic patients with coronary artery disease (CAD). METHODS To compare the postprandial lipid and glucose metabolism in normoglycemic patients with and without CAD, a total of 36 normoglycemic patients: 19 patients with stable CAD (CAD group, age 60.2±11.3 years) and 17 patients without CAD (Non-CAD group, age 60.4±9.6 years) were loaded with a high-fat and high-glucose test meal, and the changes in serum level of the lipid and glucose parameters were monitored before and 0, 2, 4, and 6h later. RESULTS In the Non-CAD group, postprandial serum levels of triglycerides (TG) and remnant-like particle cholesterol increased significantly and reached peak levels at the 4th hour and decreased significantly at the 6th hour of observation, whereas those levels in CAD group kept rising during 6h of observation. Although there was no significant difference in the area under the curves (AUCs) for the postprandial plasma glucose levels between CAD and Non-CAD group, the AUCs for the postprandial plasma insulin and C-peptide levels were significantly higher in the CAD group than in the Non-CAD group. The AUCs for postprandial TG levels showed good correlation with those for postprandial plasma insulin and C-peptide levels (insulin: r=0.455, p<0.005; C-peptide: r=0.462, p<0.05). CONCLUSIONS These findings suggest that postprandial hyperlipidemia and hyperinsulinemia may have a close relationship in CAD patients without DM and might play an important role in the development of atherosclerosis even before the onset of diabetes.

Comparison of the measured pre-ejection periods and left ventricular ejection times between echocardiography and impedance cardiography for optimizing cardiac resynchronization therapy

The pre‐ejection period (PEP) and left ventricular ejection time (LVET) are easily measured by impedance cardiography (ICG). We hypothesized that the PEP/LVET measured by ICG would correlate with that measured by echocardiography, and that PEP/LVET measured by ICG would be useful for cardiac resynchronization therapy (CRT) optimization.

Stent implantation and optical frequency domain imaging with carbon dioxide for chronic total occlusion in the superficial femoral artery

A 68-year-old female was presented with claudication in the left lower leg. She underwent angiography with carbon dioxide (CO2) because she had a history of anaphylactic shock to iodinated contrast medium. It revealed total occlusion of the left superficial femoral artery (SFA), and subsequently endovascular therapy (EVT) was performed by an antegrade approach from the left common femoral artery. After stent implantation, we performed optical frequency domain imaging (OFDI) using CO2 as contrast medium. OFDI has been extensively studied in the coronary circulation; however, its use in the peripheral arterial circulation is scarce. We present a case of stent implantation and OFDI using CO2 as an ancillary tool during EVT for SFA lesions in the patient with contraindication to iodinated contrast medium.