For the past century, the renin-angiotensin system (RAS) has been recognized as one of the major blood pressure-regulating systems. Angiotensin II (Ang II) is the final physiologically active product ...of RAS, and it works not only as a strong vasopressor but also as a promotor of tissue remodeling in various organs such as heart, arteries, and kidneys. RAS is the predominant pathway of Ang II formation in human plasma, but not in the tissues. There are several alternative pathways producing angiotensin II in human tissues, and they are involved in structural remodeling of the cardiovascular system. Proteinases such as chymase, kallikrein, cathepsin G, and elastase-2 are probably responsible for angiotensin-converting enzyme (ACE)-independent Ang II formation in human tissues. In particular, chymase is an important Ang II-generating enzyme in the human heart. It is important to elucidate the mechanisms of the ACE-independent Ang II formation in human tissues; long-term inhibition of the local Ang II formation may become one of the strategies to prevent cardiovascular remodeling.
Background: It has been suggested that anti-smoking therapy gives encouraging results, but this has not been verified by well-randomized study protocols. The present study was a randomized controlled ...trial of varenicline vs nicotine patch in adult smokers for comparison of efficacy, safety and withdrawal symptoms. Methods and Results: The 32 adult smokers were randomly divided into a varenicline group (VG, n=16) and a nicotine patch group (NG, n=16). The primary endpoints were the 12- and 24-week smoking-abstinence rates, safety and withdrawal symptoms including stress. No significant difference in abstinence rates was observed between the 2 groups over weeks 9-12 (71.4% vs 78.6% in the VG and NG, respectively), and weeks 9-24 (64.3% vs 71.4%, respectively). The frequencies of inability to concentrate at 2, 4, and 8 weeks, and wakeful nights at 2 weeks were higher in the VG than in the NG. Adverse side-effects associated with a gastrointestinal disorder occurred in 14 cases and 1 case in the VG and NG, respectively, and skin allergy was seen in 0 and 9 cases, respectively. Conclusions: The selection of treatment depends on the balance of desired acuteness of cessation of smoking and side-effects, such as psychiatric and gastrointestinal problems or skin allergy. (Circ J 2010; 74: 771-778)
Chronic kidney disease (CKD) is well known to be associated with an increased incidence of coronary artery disease (CAD). Diabetes mellitus (DM) and hypertension (HTN), both of which are traditional ...risk factors for CAD, are the two most common causes of CKD. However, the influence of CKD on coronary atherosclerosis in CAD patients who have both DM and HTN remains uncertain. In these patients, we examined the relationship between CKD and coronary plaque using integrated backscatter intravascular ultrasound (IB IVUS). Two hundred two CAD patients with both DM and HTN who underwent percutaneous coronary intervention using IB IVUS were included. The patients were divided into two groups: CKD group (
n
= 106) and non-CKD group (
n
= 96). Gray-scale and IB IVUS examinations were conducted for the non-culprit segment of a coronary artery. As a result, although there was no significant difference in the percentage of plaque volume, the percentage of lipid volume was significantly higher in the CKD group than in the non-CKD group median (IQR): 56.7% (45.4–67.0%) vs. 52.0% (38.3–60.2%),
p
= 0.03. In all of the patients, estimated glomerular filtration rate levels were negatively correlated with the percentage of lipid volume (
r
= − 0.15,
p
= 0.03) and positively correlated with the percentage of fibrosis volume (
r
= 0.15,
p
= 0.04). A multivariate regression analysis showed that CKD was an independent predictor associated with the increased lipid volume (
β
= 0.15,
p
= 0.047) and decreased fibrosis volume (
β
= − 0.16,
p
= 0.03) in coronary plaques. In conclusion, among CAD patients who had both DM and HTN, CKD was associated with lipid-rich coronary plaques. CKD may contribute to the vulnerability of coronary plaque in these very high-risk patients.
Smoking promotes arteriosclerosis and is one of the most important coronary risk factors. However, few studies have investigated the association between smoking habits and the severity of coronary ...stenosis as assessed by coronary computed tomography angiography (CTA). We enrolled 416 patients 165/251 = smoker (past and current)/non-smoker). They had all undergone CTA and either were clinically suspected of having coronary artery disease (CAD) or had at least one cardiovascular risk factor. We divided the patients into smoking and non-smoking groups, and evaluated the presence of CAD, the number of significantly stenosed coronary vessels (VD), and the Gensini score as assessed by CTA in the two groups. The incidence of CAD, VD, the Gensini score, and coronary calcification score in the smoking group were all significantly greater than those in the non-smoking group (CAD,
p
= 0.009; VD,
p
= 0.003; Gensini score,
p
= 0.007; coronary calcification score,
p
= 0.01). Pack-year was significantly associated with VD and the Gensini score, and was strongly associated with multi-vessel disease (2- and 3-VD) (
p
< 0.05), whereas the duration of cessation in past smokers was not associated with VD or the Gensini score. Pack-year, but not the duration of cessation, may be the most important factor that was associated with the severity of coronary stenosis in terms of VD and the Gensini score.
Cholesterol efflux is a major atheroprotective function of high-density lipoproteins (HDLs) which removes cholesterol from the foam cells of lipid-rich plaques in Type 2 diabetes. The dipeptidyl ...peptidase-4 (DPP-4) inhibitor sitagliptin phosphate increases plasma glucagon-like peptide-1 (GLP-1) concentrations and is used to treat Type 2 diabetes. GLP-1 plays an important role in regulating insulin secretion and expression via the GLP-1 receptor (GLP-1R), which is expressed in pancreatic islets as well as freshly isolated human monocytes and THP-1 cells. Here, we identified a direct role of GLP-1 and DPP-4 inhibition in HDL function. Cholesterol efflux was measured in cultivated phorbol 12-myristate 13-acetate-treated THP-1 cells radiolabeled with
H-cholesterol and stimulated with liver X receptor/retinoid X receptor agonists. Contrary to vildagliptin, sitagliptin phosphate together with GLP-1 significantly (
< 0.01) elevated apolipoprotein (apo)A1-mediated cholesterol efflux in a dose-dependent manner. The sitagliptin-induced increase in cholesterol efflux did not occur in the absence of GLP-1. In contrast, adenosine triphosphate-binding cassette transporter A1 (ABCA1) mRNA and protein expressions in the whole cell fraction were not changed by sitagliptin in the presence of GLP-1, although sitagliptin treatment significantly increased ABCA1 protein expression in the membrane fraction. Furthermore, the sitagliptin-induced, elevated efflux in the presence of GLP-1 was significantly decreased by a GLP-1R antagonist, an effect that was not observed with a protein kinase A inhibitor. To our knowledge, the present study reports for the first time that sitagliptin elevates cholesterol efflux in cultivated macrophages and may exert anti-atherosclerotic actions that are independent of improvements in glucose metabolism. Our results suggest that sitagliptin enhances HDL function by inducing a de novo HDL synthesis via cholesterol efflux.
•Powdered young leaves or young leaves extract of Polygonum hydropiper Linn. showed depressor effect in salt-induced hypertensive WT mice.•Powdered young leaves of Polygonum hydropiper at its maximum ...dose 500 mg kg−1 produced remarkable suppression of high blood pressure.•Polygonum hydropiper young leaves extract at its maximum dose 20 mg kg−1 showed greater suppression of high blood pressure.
A novel chymase inhibitor has been reported to have depressor effect in salt-induced hypertension. Therefore, we examined the hypothesis that chymase inhibitory dried young leaves of Polygonum hydropiper (PPH) or young leaves extract of Polygonum hydropiper (PHE) could reduce salt-induced hypertension. In this study, 8-wk old wild-type mice were allocated into three experiments and experiment I included groups, I- normal water drinking, II- high salt (2% NaCl) water (HSW) drinking, and III- HSW plus PPH (500 mg kg−1, orally) for 12-wk. Blood pressure (BP) and heart rate (HR) were measured at baseline and weekly up to wk-12. In experiment II, mice were given HSW for 12-wk followed by 8-wk treatment with PPH plus HSW (62.5, 125, 250 and 500 mg kg−1 for groups I, II, III and IV, respectively). BP and HR were measured at baseline and monthly until wk-12, following weekly for 8-wk. Experiment III comprised of four groups of mice for 12-wk HSW and 8-wk treatment with PHE plus HSW (2.5, 5, 10 and 20 mg kg−1 for groups I–IV, respectively). BP and HR were measured at baseline and monthly up to wk-12, following weekly for 8-wk. Significant reduction in BP and HR were observed in mice treated with PPH (500 mg kg−1) compared to HSW control. PPH reduced BP and HR dose dependently in hypertensive mice and the higher dose showed maximum reduction. PHE at its maximum dose (20 mg kg−1) significantly suppressed BP and HR. Over all, we found that the young leaves of Polygonum hydropiper suppressed salt-induced hypertension.
Objective: Most important lifestyle factor for the primary and secondary prevention for coronary heart diseases is smoking. However, few reported on the relationship between smoking habits/history ...and long-term outcomes post PCI procedures. Methods: From our PCI- Registry (FU-Registry), 829 PCI cases (497 males, 332 females) whose 5 years follow-up data including clinical outcomes were available, were used. Results: In males, no difference was observed in patient’s background or lesion characteristics between smoker and never smoker groups, however, smoking (+) showed high incidence of dyslipidemia, statin use at first PCI, but as for clinical outcomes are similar between the groups. For females, smoking (+) group showed low HDL-C (48.3 +12.8mg/dL vs. 51.5+13.4mg/dL, p< 0.01), and lesion reference was significantly smaller than smoking (-) group. No difference was observed in medications, while smoking (+) showed high complication of ASO. Conclusions: Females were less smokers than males, while female smokers showed low HDL-C levels at PCI and then longterm outcomes (including MACEs) were more frequent in smokers than never smokers.
Lysophosphatidic acid (LPA) is a lipid mediator with multiple biological activities that accounts for many biological properties of serum. LPA is thought to be produced during serum formation based ...on the fact that the LPA level is much higher in serum than in plasma. In this study, to better understand the pathways of LPA synthesis in serum, we evaluated the roles of platelets, plasma, and phospholipases by measuring LPA using a novel enzyme-linked fluorometric assay. First, examination of platelet-depleted rats showed that half of the LPA in serum is produced via a platelet-dependent pathway. However, the amount of LPA released from isolated platelets after they are activated by thrombin or calcium ionophore accounted for only a small part of serum LPA. Most of the platelet-derived LPA was produced in a two-step process: lysophospholipids such as lysophosphatidylcholine (LPC), lysophosphatidylethanolamine, and lysophosphatidylserine, were released from activated rat platelets by the actions of two phospholipases, group IIA secretory phospholipase A(2) (sPLA(2)-IIA) and phosphatidylserine-specific phospholipase A(1) (PS-PLA(1)), which were abundantly expressed in the cells. Then these lysophospholipids were converted to LPA by the action of plasma lysophospholipase D (lysoPLD). Second, accumulation of LPA in incubated plasma was strongly accelerated by the addition of recombinant lysoPLD with a concomitant decrease in LPC accumulation, indicating that the enzyme produces LPA by hydrolyzing LPC produced during the incubation. In addition, incubation of plasma isolated from human subjects who were deficient in lecithin-cholesterol acyltransferase (LCAT) did not result in increases of either LPC or LPA. The present study demonstrates multiple pathways for LPA production in serum and the involvement of several phospholipases, including PS-PLA(1), sPLA(2)-IIA, LCAT, and lysoPLD.
Patients with type 2 diabetes mellitus (DM) exhibit modification of high-density lipoprotein (HDL), which is likely to have an important role in the development of atherosclerotic cardiovascular ...disease (ASCVD). Excess production of aldosterone (Ald) results in hypertension as well as ASCVD. However, the biological activity of modified HDL in steroidogenesis is not clear. We measured the accumulation of thiobarbituric acid-reactive substances (TBARSs) and Nɛ-(carboxymethyl)lysine (CML) levels (markers of oxidation and glycoxidation, respectively) in isolated HDL from 41 patients with type 2 diabetes mellitus (DM group) and 41 age- and gender-matched patients in a non-DM group. We quantified angiotensin II-sensitized and -nonsensitized Ald release using a validated living adrenocortical cell assay. TBARS levels in isolated HDL were similar between patients in the DM and non-DM groups, whereas the CML content of HDL in the DM group was lower than that in the non-DM group, irrespective of higher blood glucose and hemoglobin A1c levels. There was no difference in the HDL-induced ex vivo Ald release between the groups. Although sustained hyperglycemia was not a determinant of HDL-induced Ald release, the degree of HDL glycoxidation was inversely associated with HDL-induced Ald release (r=-0.40, P<0.001). In conclusion, in vivo advanced glycoxidation of HDL had an inverse effect on HDL-induced Ald release, independent of the prevalence of type 2 DM.
PDF
