The association of C-reactive protein with an oxidative metabolite of LDL and its implication in atherosclerosis

C-reactive protein (CRP) is one of the strongest independent predictors of cardiovascular disease. We have previously reported that oxidized LDL (oxLDL) interacts with beta 2-glycoprotein I (beta 2GPI), implicating oxLDL/P2GPI complexes as putative autoantigens in autoimmune-mediated atherosclerotic vascular disease. In this study, we investigated the interaction of CRP with oxLDL/beta 2GPI complexes and its association with atherosclerosis in patients with diabetes mellitus (DM). CRP/oxLDL/R2GPI complexes were predominantly found in sera of DM patients with atherosclerosis. In contrast, noncomplexed CRP isoforms were present in sera of patients with acute/chronic inflammation, i.e., various pyrogenic diseases, rheumatoid arthritis (RA), and DM. Immunohistochemistry staining colocalized CRP and beta 2GPI together with oxLDL in carotid artery plaques but not in synovial tissue from RA patients, strongly suggesting that complex formation occurs during the development of adierosclerosis. Serum levels of CRP correlated with soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and oxLDL/beta 2GPI complexes correlated with total cholesterol and hemoglobin Al c. Thus, the generation of CRP/oxLDL/beta 2GPI complexes seems to be associated with arterial inflammation, hyperglycemia, and hypercholesterolemia. CRP/oxLDL/R2GPI complexes can be distinguished from pyrogenic noncomplexed CRP isoforms and may represent a more specific and predictive marker for atherosclerosis

Calcium Channel Blockers, More than Diuretics, Enhance Vascular Protective Effects of Angiotensin Receptor Blockers in Salt-Loaded Hypertensive Rats

The combination therapy of an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB) or with a diuretic is favorably recommended for the treatment of hypertension. However, the difference between these two combination therapies is unclear. The present work was undertaken to examine the possible difference between the two combination therapies in vascular protection. Salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP) were divided into 6 groups, and they were orally administered (1) vehicle, (2) olmesartan, an ARB, (3) azelnidipine, a CCB, (4) hydrochlorothiazide, a diuretic, (5) olmesartan combined with azelnidipine, or (6) olmesartan combined with hydrochlorothiazide. Olmesartan combined with either azelnidipine or hydrochlorothiazide ameliorated vascular endothelial dysfunction and remodeling in SHRSP more than did monotherapy with either agent. However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP. The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS) pathway. These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB

コウ ショクエン フカ ニ ヨル シン ケッカン ビョウヘン ワ ASK 1 ケッソン ニ ヨリ ケイゲン サレル

食塩の過剰摂取と心血管イベントと関わりは古くから指摘されているが、その詳細なメカニズムは未だ不明な点が多い。本研究では、正常血圧のマウスにおける高食塩負荷による心血管障害と、ストレス応答性のMAPKKKである、apoptosis signal-regulating kinase (ASK)1の関連性について明らかにすることを目的とした

Potential Therapeutic Targets and Promising Agents for Combating NAFLD

Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is a growing cause of liver cirrhosis and liver cancer worldwide because of the global increases in obesity, dyslipidemia, hypertension, and type 2 diabetes mellitus. Contrary to the advancements in therapies for viral hepatitis, effective treatments remain unestablished for patients with NAFLD. NAFLD, including NASH, is characterized by steatosis, inflammation, hepatic necrosis, and fibrosis. Despite our understanding of its pathophysiology, there are currently no effective treatments for NAFLD. In this review, we provide an update on the known pathophysiological mechanisms involved in the development of NAFLD and the role of hepatic stellate cells, and summarize the potential therapeutic agents, including natural products, for NAFLD

Measurement of nuclear reaction cross sections by using Cherenkov radiation toward high-precision proton therapy

Monitoring the in vivo dose distribution in proton therapy is desirable for the accurate irradiation of a tumor. Although positron emission tomography (PET) is widely used for confirmation, the obtained distribution of positron emitters produced by the protons does not trace the dose distribution due to the different physical processes. To estimate the accurate dose from the PET image, the cross sections of nuclear reactions that produce positron emitters are important yet far from being sufficient. In this study, we measured the cross sections of 16O(p,x)15O, 16O(p,x)13N, and 16O(p,x)11C with a wideenergy range (approximately 5–70 MeV) by observing the temporal evolution of the Cherenkovradiation emitted from positrons generated via β+ decay along the proton path. Furthermore, we implemented the new cross sectional data into a conventional Monte Carlo (MC) simulation, so that a direct comparison was possible with the PET measurement. We confirmed that our MC results showed good agreement with the experimental data, both in terms of the spatial distributions and temporalevolutions. Although this is the first attempt at using the Cherenkov radiation in the measurements of nuclear cross sections, the obtained results suggest the method is convenient and widely applicable for high precision proton therapy

Characterization of smooth muscle-like cells in circulating human peripheral blood

Smooth muscle cells play an important role in human vascular diseases. Several lines of evidence demonstrate that circulating smooth muscle precursor cells contribute to intimal hyperplasia in animal models. We obtained large spindle cells expressing alpha-smooth muscle actin (α-SMA), denoted here as “smooth muscle-like cells” (SMLC), from human peripheral blood mononuclear cells (PBMC). SMLC derived from human PBMC proliferated readily and expressed pro-inflammatory genes during early culture. After long-term culture, SMLC could contract and express characteristic smooth muscle cell markers. We found peripheral blood mononuclear cell expressing α-smooth muscle actin in the circulating blood that bore CD14 and CD105. Sorted CD14/CD105 double-positive PBMC could differentiate into SMLC. The number of CD14–CD105-bearing PBMC increased significantly in patients with coronary artery disease compared to patients without coronary artery disease. These results support the novel concept that smooth muscle precursor cells exist in circulating human blood and may contribute to the pathogenesis of vascular diseases