ABSTRACT
Ophiocordyceps sinensis (OCS), an entomopathogenic fungus, is known to exert antiproliferative and antitissue remodeling effects. Vascular remodeling and vasoconstriction play critical roles in the development of pulmonary hypertension (PH). The therapeutic potential of OCS for PH was investigated using rodent PH models, and cultured pulmonary artery endothelial and smooth muscle cells (PAECs and PASMCs), with a focus on the involvement of TRPM7. OCS ameliorated the development of PH, right ventricular hypertrophy and dysfunction in the monocrotaline-induced PH rats. The genetic knockout of TRPM7 attenuated the development of PH in mice with monocrotaline pyrrole-induced PH. TRPM7 was associated with medial hypertrophy and the plexiform lesions in rats and humans with PH. OCS suppressed proliferation of PASMCs derived from the PH patients. Ethanol extracts of OCS inhibited TRPM7-like current, TGF-ß2-induced endothelial-mesenchymal transition, IL-6-induced STAT3 phosphorylation, and PDGF-induced Akt phosphorylation in PAECs or PASMCs. These inhibitory effects were recapitulated by either siRNA-mediated TRPM7 knockdown or treatment with TRPM7 antagonist FTY-720. OCS and FTY-720 induced vasorelaxation in the isolated normal human pulmonary artery. As a result, the present study proposes the therapeutic potential of OCS for the treatment of PH. The inhibition of TRPM7 is suggested to underlie the therapeutic effect of OCS.
Subject(s)
Cordyceps/physiology , Hypertension, Pulmonary/physiopathology , Hypertension, Pulmonary/therapy , TRPM Cation Channels/antagonists & inhibitors , Animals , Cell Proliferation , Cells, Cultured , Disease Models, Animal , Fingolimod Hydrochloride/pharmacology , Gene Knockdown Techniques , Humans , Hypertension, Pulmonary/pathology , Male , Medicine, Chinese Traditional , Mice , Mice, Knockout , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/physiology , Proto-Oncogene Proteins c-akt/metabolism , Pulmonary Artery/pathology , Pulmonary Artery/physiopathology , Rats , Rats, Sprague-Dawley , STAT3 Transcription Factor/metabolism , TRPM Cation Channels/deficiency , TRPM Cation Channels/genetics , TRPM Cation Channels/physiology , Translational Research, Biomedical , VasodilationABSTRACT
Pulmonary arterial hypertension (PAH) is a multifactorial disease characterized by pulmonary arterial vasoconstriction and remodeling. Src family tyrosine kinases, including Fyn, play critical roles in vascular remodeling via the inhibition of STAT3 signaling. EPA is known to inhibit Fyn kinase activity. This study investigated the therapeutic potential and underlying mechanisms of EPA and its metabolite, resolvin E1 (RvE1), to treat PAH using monocrotaline-induced PAH model rats (MCT-PAH), human pulmonary artery endothelial cells (HPAECs), and human pulmonary artery smooth muscle cells (HPASMCs). Administration of EPA 1 and 2 weeks after MCT injection both ameliorated right ventricular hypertrophy, remodeling and dysfunction, and medial wall thickening of the pulmonary arteries and prolonged survival in MCT-PAH rats. EPA attenuated the enhanced contractile response to 5-hydroxytryptamine in isolated pulmonary arteries of MCT-PAH rats. Mechanistically, the treatment with EPA and RvE1 or the introduction of dominant-negative Fyn prevented TGF-ß2-induced endothelial-to-mesenchymal transition and IL-6-induced phosphorylation of STAT3 in cultured HPAECs. EPA and RvE1 suppressed Src family kinases' activity as evaluated by their phosphorylation status in cultured HPAECs and HPASMCs. EPA and RvE1 suppressed vasocontraction of rat and human PA. Furthermore, EPA and RvE1 inhibited the enhanced proliferation and activity of Src family kinases in HPASMCs derived from patients with idiopathic PAH. EPA ameliorated PAH's pathophysiology by mitigating vascular remodeling and vasoconstriction, probably inhibiting Src family kinases, especially Fyn. Thus, EPA is considered a potent therapeutic agent for the treatment of PAH.
Subject(s)
Eicosapentaenoic Acid/therapeutic use , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/enzymology , Proto-Oncogene Proteins c-fyn/antagonists & inhibitors , Animals , Cell Proliferation/drug effects , Eicosapentaenoic Acid/analogs & derivatives , Eicosapentaenoic Acid/pharmacology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelial Cells/pathology , Endothelium, Vascular/drug effects , Endothelium, Vascular/pathology , Endothelium, Vascular/physiopathology , Humans , Hypertension, Pulmonary/physiopathology , Hypertrophy, Right Ventricular/complications , Hypertrophy, Right Ventricular/physiopathology , Interleukin-6/pharmacology , Male , Mesoderm/drug effects , Mesoderm/pathology , Mesoderm/physiopathology , Monocrotaline , Myocardial Contraction/drug effects , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/metabolism , Phosphorylation/drug effects , Proto-Oncogene Proteins c-fyn/metabolism , Pulmonary Artery/drug effects , Pulmonary Artery/physiopathology , Rats, Sprague-Dawley , STAT3 Transcription Factor/metabolism , Survival Analysis , Transforming Growth Factor beta2/pharmacology , Vasodilation/drug effects , Ventricular Remodeling/drug effects , src-Family Kinases/metabolismABSTRACT
In the Original publication of the article, the legend appearing inside the flow chart has been incorrectly published.
ABSTRACT
There is a lack of data on how to treat hypertensive patients with diabetes when treatment with medium doses of calcium channel blocker and angiotensin II type 1 receptor blocker (ARB) is insufficient to achieve the target blood pressure (BP). A total of 121 participants with type 2 diabetes and uncontrolled essential hypertension, who were receiving medium doses of amlodipine (5 mg/day) and ARB, were enrolled. Participants were randomized to receive either a high dose of amlodipine (10 mg/day) plus a medium dose of ARB (high-AML) or a medium dose of amlodipine (5 mg/day) plus a high dose of ARB (high-ARB). The depressor effects of these two regimens were monitored using a telemonitoring home BP-measuring system. Fifty-four patients were excluded after an observation period, and the remaining 67 eligible participants were randomized into the two groups; 42 which had a record of their home BP for analysis. The change in morning home systolic and diastolic BP was greater in the high-AML than in the high-ARB (systolic BP; - 7.9 mmHg vs. + 2.7 mmHg; p = 0.0002, diastolic BP; - 3.9 mmHg vs. + 0.6 mmHg; p = 0.0007). In addition, the home systolic and diastolic BP before going to bed and office systolic BP were significantly reduced from week 0 only in the high-AML. An increased dose of amlodipine, but not ARB, reduced home morning BP in hypertensive patients with type 2 diabetes who were already receiving combination therapy with medium doses of amlodipine and ARB.
Subject(s)
Amlodipine/administration & dosage , Angiotensin II Type 1 Receptor Blockers/administration & dosage , Blood Pressure/physiology , Diabetes Mellitus, Type 2/complications , Essential Hypertension/drug therapy , Aged , Blood Pressure/drug effects , Blood Pressure Monitoring, Ambulatory , Calcium Channel Blockers/administration & dosage , Diabetes Mellitus, Type 2/drug therapy , Dose-Response Relationship, Drug , Drug Therapy, Combination , Essential Hypertension/complications , Essential Hypertension/physiopathology , Female , Follow-Up Studies , Humans , Male , Treatment OutcomeABSTRACT
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 (500â¯mgâ¯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 500â¯mgâ¯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 20â¯mgâ¯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 (500â¯mgâ¯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 (20â¯mgâ¯kg-1) significantly suppressed BP and HR. Over all, we found that the young leaves of Polygonum hydropiper suppressed salt-induced hypertension.
Subject(s)
Hypertension/drug therapy , Plant Extracts/therapeutic use , Plant Leaves/chemistry , Polygonum/chemistry , Sodium Chloride/adverse effects , Animals , Blood Pressure/drug effects , Body Weight/drug effects , Diastole/drug effects , Heart Rate/drug effects , Hypertension/physiopathology , Male , Mice, Inbred C57BL , Plant Extracts/pharmacology , Systole/drug effectsABSTRACT
We examined whether tolvaptan combined with an angiotensin II receptor blocker (ARB) or angiotensin converting enzyme inhibitor (ACE-I) is more effective than tolvaptan alone in the treatment of patients with heart failure (HF). Sixty-five hospitalized patients with acute decompensated HF were included in this study. They were divided into 2 groups; an ARB/ACE-I group (n = 44, who received ARB or ACE-I before the use of tolvaptan) and a non-ARB/ACE-I group (n = 21). There were no significant differences in patient characteristics including medications at baseline between the non-ARB/ACE-I and ARB/ACE-I groups with the exception of the percentages of hypertension and ischemic heart disease. Urinary volume (UV) at baseline in the ARB/ACE-I group was slightly higher than that in the non-ARB/ACE-I group. The increase in UV after the use of tolvaptan in the non-ARB/ACE-I group was significantly higher than that in the ARB/ACE-I group. The cardiothoracic ratio and the reduction in body weight were similar between the groups after tolvaptan use. Finally, in a logistic regression analysis, a response to the use of tolvaptan was independently associated with the non-use of ARB/ACE-I, but not with age, gender, body mass index, loop diuretic, or human arterial natriuretic peptide. In conclusion, tolvaptan alone might induce an increase in UV in decompensated HF patients without ARB/ ACE-I, although the treatment of HF with ARB/ACE-I is the first choice strategy.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Benzazepines/administration & dosage , Heart Failure/drug therapy , Acute Disease , Aged , Antidiuretic Hormone Receptor Antagonists/administration & dosage , Dose-Response Relationship, Drug , Drug Therapy, Combination , Female , Heart Failure/physiopathology , Humans , Male , Retrospective Studies , Tolvaptan , Treatment Outcome , Urination/drug effectsABSTRACT
BACKGROUND: In our experience, the change in body weight (BW) during hospitalization varies greatly in patients with acute decompensated heart failure (HF). Since the clinical significance of a change in BW is not clear, we investigated whether a change in BW could predict mortality. METHODS: We retrospectively enrolled 130 patients (72 males; aged 68 ± 10 years) who were hospitalized due to acute decompensated HF and followed for 2 years after discharge. The change in the BW index during hospitalization (ΔBWI) was calculated as (BW at hospital admission minus BW at hospital discharge)/body surface area at hospital discharge. RESULTS: The patients were divided into quartiles according to ΔBWI, and the 2-year mortality rates in the quartiles with the lowest, second, third and highest ΔBWI were 18.8%, 12.1%, 3.1% and 9.1%, respectively. In a multivariate Cox proportional hazards analysis after adjusting for variables with a P value less than 0.05, ΔBWI was independently associated with 2-year mortality (P = 0.0002), and the quartile with the lowest ΔBWI had a higher relative risk (RR) for 2-year mortality than the quartile with the highest ΔBWI (RR: 7.46, 95% confidence interval: 1.03 - 53.99, P = 0.04). CONCLUSION: In conclusion, ΔBWI was significantly associated with 2-year mortality after discharge, which indicates that ΔBWI might be a simple predictor of prognosis in acute decompensated HF.
ABSTRACT
Angiotensin II (Ang II) modulates blood pressure and atherosclerosis development through its vascular type-1 (AT1R) and type-2 (AT2R) receptors, which have opposing effects. AT2R activation produces hypotension, and is anti-atherogenic. Targeted overexpression of AT2Rs in vascular smooth muscle cells (VSMCs) indicates that these effects are due to increased nitric oxide (NO) generation. However, the role of endogenous VSMC AT2Rs in these events is unknown. Effect of 7-day low-dose Ang II-infusion (12 µg/kg/hr) on blood pressure was tested in 9-week-old apoE((-/-)) mice fed a low or high cholesterol diet (LCD or HCD, respectively). Cardiac output was measured by echocardiography. Immunohistochemistry was performed to localize and quantify AT2Rs and p-Ser(1177)-endothelial nitric oxide synthase (eNOS) levels in the aortic arch. PD123319 and GW-9662 were used to selectively block the AT2R and peroxisome proliferator-activated receptor-γ (PPAR-γ), respectively. Ang II infusion decreased blood pressure by 12 mmHg (P < 0.001) in LCD/apoE((-/-)) mice without altering cardiac output; a response blocked by PD123319. Although, AT2R stimulation neither activated eNOS (p-Ser(1177)-eNOS) nor changed plasma NO metabolites, it caused an ~6-fold increase in VSMC PPAR-γ levels (P < 0.001) and the AT2R-mediated hypotension was abolished by GW-9662. AT2R-mediated hypotension was also inhibited by HCD, which selectively decreased VSMC AT2R expression by ~6-fold (P < 0.01). These findings suggest a novel pathway for the Ang II/AT2R-mediated hypotensive response that involves PPAR-γ, and is down regulated by a HCD.
ABSTRACT
A recent clinical study indicated that an angiotensin II (Ang II) type 1 (AT1) receptor-neprilysin inhibitor (ARNi) designated LCZ696 (sacubitril/valsartan, as combined sodium complex) was superior to enalapril at reducing the risks of death and hospitalization due to heart failure. Therefore, we investigated the possible mechanisms of the beneficial effect of LCZ696, in which the inhibition of neprilysin enhances atrial natriuretic peptide (NP) or brain NP (ANP or BNP)-evoked signals that can block Ang II/AT1 receptor-induced aldosterone (Ald) synthesis in human adrenocortical cells. The binding affinity of valsartan+LBQ657 (active moiety of sacubitril) to the AT1 receptor was greater than that of valsartan alone in an AT1 receptor-expressing human embryonic kidney cell-based assay. There was no difference in the dissociation from the AT1 receptor between valsartan+LBQ657 and valsartan alone. In Ang II-sensitized human adrenocortical cells, ANP or BNP alone, but not LBQ657 or valsartan alone, significantly decreased Ald synthesis. The level of suppression of Ald synthesis by ANP or BNP with LBQ657 was greater than that by ANP or BNP without LBQ657. The suppression of ANP was blocked by inhibitors of regulator of G-protein signaling proteins and cyclic GMP-dependent protein kinase. The inhibition of neprilysin did not change the mRNA levels of the AT1 receptor, ANP receptor A, regulator of G-protein signaling protein, renin or 3ß-hydroxysteroid dehydrogenases. In conclusion, the inhibition of neprilysin by LBQ657 enhances the NP-evoked signals that can block Ang II/AT1 receptor-induced Ald synthesis in human adrenocortical cells.
Subject(s)
Adrenal Cortex/drug effects , Aldosterone/biosynthesis , Aminobutyrates/pharmacology , Angiotensin Receptor Antagonists/pharmacology , Tetrazoles/pharmacology , Adrenal Cortex/cytology , Adrenal Cortex/metabolism , Angiotensin II Type 1 Receptor Blockers/pharmacology , Biphenyl Compounds , Cell Line , Drug Combinations , Humans , Neprilysin/antagonists & inhibitors , Receptor, Angiotensin, Type 1/metabolism , Valsartan/pharmacologyABSTRACT
BACKGROUND: To improve the clinical outcome of heart failure (HF), it is important to evaluate the etiology and comorbidities of HF. We previously reported the baseline clinical characteristics and medications in hospitalized patients with HF in years 2000 - 2002 (group 2000) and 2007 - 2009 (group 2008). METHODS: We conducted a retrospective study of 158 patients who were hospitalized due to HF between 2012 and 2014 (group 2013) in the Department of Cardiology, Fukuoka University Hospital. We analyzed the clinical characteristics and medications at admission and discharge, and compared the findings in group 2013 to those in group 2000 and group 2008. RESULTS: The major causes of HF were ischemic heart disease, hypertensive cardiomyopathy, valvular heart disease, and dilated cardiomyopathy. The New York Heart Association classification in group 2013 was significantly higher than those in group 2000 and group 2008. There was no difference in the level of brain natriuretic peptide at admission between group 2008 and group 2013. Tolvaptan began to be administered in group 2013. The median dose of furosemide just before the use of tolvaptan was 40 mg/day. At discharge, group 2013 showed higher rates of ß-blocker and aldosterone antagonist. There was no difference in the frequency of loop diuretics. The dose of carvedilol at discharge was only 6.2 ± 4.0 mg/day. Antiarrhythmic drugs and ß-blocker were used more frequently in HF with reduced ejection fraction (EF) than in HF with preserved EF. CONCLUSIONS: We may be able to improve the clinical outcome of HF by examining the differences in the clinical characteristics and medications at admission and discharge in hospitalized patients with HF.
ABSTRACT
AIMS: Angiotensin receptor-neprilysin inhibitors (ARNis) acts an ARB and neprilysin inhibitor. Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure (HF). Therefore, we evaluated the effects and mechanisms of ARNi in HF with reduced ejection fraction (HFrEF) in streptozotocin-induced diabetic mice. METHODS AND RESULTS: Male C57BL/6J mice were injected with streptozotocin to produce diabetic mice. After myocardial reperfusion injury, diabetic mice were randomized to treatment for 4 weeks with LCZ696 (60 mg/kg), valsartan (30 mg/kg), or no treatment (n = 26-28 in each group). Cardiac function was assessed by a pressure-volume Millar catheter. The ratios of heart weight to body weight in the valsartan (P = 0.02) and LCZ696 (P = 0.005) groups were significantly less than that in the control group. Treatment with LCZ696 improved LVEF (43 ± 3.4%) with a significantly reduction of atrial natriuretic peptide mRNA in the left ventricle compared with that in the control group (29 ± 3.2%) (P = 0.006). The fibrotic area in the LCZ696 group was significantly suppressed compared with those in the control (P = 0.003) and valsartan (P = 0.04) groups. Moreover, the mRNA level of transforming growth factor-ß (TGF-ß) in the left ventricle was suppressed in the LCZ696 group compared with that in the control (P = 0.002) group. CONCLUSION: The ARNi LCZ696 improved cardiac function with the reduction of fibrosis in an HF-rEF model in diabetic mice, by suppressing TGF-ß. This effect may be due to the specific inhibition of neprilysin, beyond the ARB effect of LCZ696.
Subject(s)
Aminobutyrates/pharmacology , Angiotensin Receptor Antagonists/pharmacology , Diabetes Mellitus, Experimental , Heart Failure/physiopathology , Heart/drug effects , Myocardial Reperfusion Injury/physiopathology , Myocardium/pathology , Neprilysin/antagonists & inhibitors , Tetrazoles/pharmacology , Animals , Atrial Natriuretic Factor/drug effects , Atrial Natriuretic Factor/genetics , Biphenyl Compounds , Drug Combinations , Fibrosis , Heart/physiopathology , Heart Failure/pathology , Heart Ventricles/drug effects , Heart Ventricles/metabolism , Heart Ventricles/pathology , Heart Ventricles/physiopathology , Male , Mice , Mice, Inbred C57BL , Myocardial Reperfusion Injury/pathology , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Stroke Volume , Transforming Growth Factor beta/drug effects , Transforming Growth Factor beta/genetics , ValsartanABSTRACT
BACKGROUND/OBJECTIVE: HDL has various atheroprotective functions and improves endothelial function. Apolipoprotein A-I (apoA-I) is a major protein of HDL and plays a crucial role in HDL functions. We developed a novel apoA-I mimetic peptide, FAMP (Fukuoka University ApoA-I Mimetic Peptide). It is unclear whether an apoA-I mimetic peptide can promote neovascularization in vivo. Here, we investigated the effect of FAMP on endothelial nitric oxide synthase (eNOS) activation and angiogenesis in a murine hindlimb ischemia model. METHODS AND RESULTS: Intramuscular administration of FAMP significantly enhanced blood flow recovery and increased capillary density in the ischemic limb of mice fed a high-cholesterol diet (HCD). In a gait analysis, FAMP ameliorated functional recovery compared with that in the control group. FAMP significantly activated Akt, ERK, and eNOS phosphorylation in endothelial cells, and improved the migratory functions of human aortic endothelial cells (HAECs). LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), significantly inhibited the activation of eNOS by FAMP. FAMP had no beneficial effects on blood flow recovery in eNOS(-/-) mice. CONCLUSIONS: FAMP promoted recovery from hindlimb ischemia through a nitric oxide (NO)-related pathway by activation of a PI3K/Akt pathway. FAMP may become a new therapeutic agent for the future clinical treatment of critical limb ischemia (CLI).
Subject(s)
Apolipoprotein A-I/therapeutic use , Biomimetic Materials/therapeutic use , Hindlimb/blood supply , Ischemia/drug therapy , Nitric Oxide/metabolism , Peptide Fragments/therapeutic use , Amino Acid Sequence , Animals , Apolipoprotein A-I/genetics , Apolipoprotein A-I/pharmacology , Biomimetic Materials/pharmacology , Cells, Cultured , Hindlimb/drug effects , Humans , Ischemia/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Peptide Fragments/genetics , Peptide Fragments/pharmacology , Recovery of Function/drug effects , Recovery of Function/physiology , Signal Transduction/drug effects , Signal Transduction/physiologyABSTRACT
OBJECTIVE: We evaluated whether a novel inducible cholesterol efflux (iCE) peptide [Fukuoka University Apolipoprotein A-I Mimetic Peptide (FAMP)] protects against myocardial ischemia reperfusion injury (IRI) through a nitric oxide (NO) pathway by an improvement of high-density lipoprotein (HDL) functionality. METHODS AND RESULTS: Male C57BL6/J mice were intraperitoneally injected with phosphate buffer as a control, low-dose (10 mg/kg) or high-dose (50 mg/kg) of FAMP before 18 h of IRI (n=6-12 in each group). After 30 min of ischemia followed by 6h of reperfusion, blood pressure, and infarct size were measured and cardiac function was evaluated by a Millar catheter. FAMP significantly improved stroke volume, cardiac output, left ventricular ejection fraction, and infarct size. FAMP significantly preserved cytochrome C in the mitochondrial fraction and inhibited its release into the cytosolic fraction in the heart, but did not significantly reduce mRNA levels of monocyte chemoattractant protein-1 or interluekin-6. In a TdT-mediated dUTP nick end labeling (TUNEL) assay, FAMP significantly suppressed the appearance of TUNEL-positive nuclear. We also performed same experiments with endothelial nitric oxide synthase-knockout (eNOS-KO) mice and FAMP-induced improvements of cardiac function were not observed in eNOS-KO mice. CONCLUSIONS: FAMP activated HDL-functionality and improved cardiac function in a model of myocardial IRI. It may have anti-apoptotic effects by protecting mitochondria through a NO pathway as a pleiotropic effect.
Subject(s)
ATP Binding Cassette Transporter 1/therapeutic use , Chemokine CCL2/genetics , Gene Expression Regulation , Myocardial Reperfusion Injury/prevention & control , Nitric Oxide/metabolism , RNA/genetics , Ventricular Function, Left/physiology , Animals , Blotting, Western , Chemokine CCL2/biosynthesis , Disease Models, Animal , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal TransductionABSTRACT
While physiological levels of nitric oxide (NO) protect the endothelium and have vasodilatory effects, excessive NO has adverse effects on the cardiovascular system. Recently, new NO-releasing pharmacodynamic hybrids of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) have been developed.We analyzed whether olmesartan with NO-donor side chains (Olm-NO) was superior to olmesartan (Olm) for the control of blood pressure (BP). Although there was no significant difference in binding affinity to AT1 wild-type (WT) receptor between Olm and Olm-NO in a cell-based binding assay, the suppressive effect of Olm-NO on Ang II-induced inositol phosphate (IP) production was significantly weaker than that of Olm in AT1 WT receptor-expressing cells. While Olm had a strong inverse agonistic effect on IP production, Olm-NO did not. Next, we divided 18 C57BL mice into 3 groups: Ang II (infusion using an osmotic mini-pump) as a control group, Ang II (n = 6) + Olm, and Ang II (n = 6) + Olm-NO groups (n = 6). Olm-NO did not block Ang II-induced high BP after 10 days, whereas Olm significantly decreased BP. In addition, Olm, but not Olm-NO, significantly reduced the ratio of heart weight to body weight (HW/BW) with downregulation of the mRNA levels of atrial natriuretic peptide.An ARB with a NO-donor may cancel BP-lowering effects probably due to excessive NO and a weak blocking effect by Olm-NO toward AT1 receptor activation.
Subject(s)
Blood Pressure/drug effects , Hypotension , Imidazoles , Tetrazoles , Angiotensin II Type 1 Receptor Blockers/chemistry , Angiotensin II Type 1 Receptor Blockers/pharmacology , Animals , Cell Culture Techniques , Hypotension/chemically induced , Hypotension/metabolism , Hypotension/prevention & control , Imidazoles/chemistry , Imidazoles/pharmacology , Inositol Phosphates/metabolism , Mice , Mice, Inbred C57BL , Nitric Oxide/metabolism , Nitric Oxide Donors/chemistry , Nitric Oxide Donors/pharmacology , Tetrazoles/chemistry , Tetrazoles/pharmacologyABSTRACT
The aim of the present study was to determine whether long-term high salt intake in the drinking water induces hypertension in wild-type (WT) mice and whether a chymase inhibitor or other antihypertensive drugs could reverse the increase of blood pressure. Eight-week-old male WT mice were supplied with drinking water containing 2% salt for 12 wk (high-salt group) or high-salt drinking water plus an oral chymase inhibitor (TPC-806) at four different doses (25, 50, 75, or 100 mg/kg), captopril (75 mg/kg), losartan (100 mg/kg), hydrochlorothiazide (3 mg/kg), eplerenone (200 mg/kg), or amlodipine (6 mg/kg). Control groups were given normal water with or without the chymase inhibitor. Blood pressure and heart rate gradually showed a significant increase in the high-salt group, whereas a dose-dependent depressor effect of the chymase inhibitor was observed. There was also partial improvement of hypertension in the losartan- and eplerenone-treated groups but not in the captopril-, hydrochlorothiazide-, and amlodipine-treated groups. A high salt load significantly increased chymase-dependent ANG II-forming activity in the alimentary tract. In addition, the relative contribution of chymase to ANG II formation, but not actual average activity, showed a significant increase in skin and skeletal muscle, whereas angiotensin-converting enzyme-dependent ANG II-forming activity and its relative contribution were reduced by high salt intake. Plasma and urinary renin-angiotensin system components were significantly increased in the high-salt group but were significantly suppressed in the chymase inhibitor-treated group. In conclusion, 2% salt water drinking for 12 wk caused moderate hypertension and activated the renin-angiotensin system in WT mice. A chymase inhibitor suppressed both the elevation of blood pressure and heart rate, indicating a definite involvement of chymase in salt-sensitive hypertension.
Subject(s)
Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Chymases/antagonists & inhibitors , Hypertension/drug therapy , Serine Proteinase Inhibitors/pharmacology , Sodium Chloride, Dietary , Albuminuria/enzymology , Albuminuria/prevention & control , Aldosterone/blood , Aldosterone/urine , Angiotensin II/blood , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensinogen/urine , Animals , Calcium Channel Blockers/pharmacology , Chymases/metabolism , Disease Models, Animal , Diuretics/pharmacology , Heart Rate/drug effects , Hypertension/enzymology , Hypertension/physiopathology , Male , Mice, Inbred C57BL , Mineralocorticoid Receptor Antagonists/pharmacology , Renin-Angiotensin System/drug effects , Time FactorsABSTRACT
BACKGROUND: The visit-to-visit variability in blood pressure (BP) has been shown to be a strong predictor of cardiovascular events. It is not known whether anti-hypertensive therapy using a single-pill fixed-dose combination of angiotensin II receptor blocker (ARB)/calcium channel blocker (CCB) or ARB/diuretic (DI) in hypertensive patients affects the visit-to-visit variability and seasonal variation of BP. METHODS: We enrolled 47 hypertensive patients who had received a single-pill fixed-dose combination of either ARB/CCB (n = 30) or ARB/DI (n = 17) for 15 months. Beginning 3 months after the start of ARB/CCB or ARB/DI treatment, we determined the visit-to-visit variability in BP expressed as the standard deviation (SD) of average BP and the seasonal variation in BP expressed as the SD of average BP in each season (spring, summer, fall and winter were defined as lasting from March to May, June to August, September to November and December to February, respectively) for a year. RESULTS: There were no significant differences in baseline patient characteristics except for the prevalence of coronary artery disease and the percentage of CCB excluding amlodipine in the ARB/CCB group between the ARB/CCB and ARB/DI groups. There were no significant differences in the 1-year time course of systolic and diastolic BP (SBP and DBP) between the groups, although there were significant differences in SBP in August and November and DBP in December. Interestingly, the visit-to-visit variability and seasonal variation of BP in the ARB/CCB group were similar to those in the ARB/DI group. CONCLUSION: Single-pill fixed-dose combinations of ARB/CCB and ARB/DI had similar effects on visit-to-visit variability and seasonal variation in BP in hypertensive patients.
ABSTRACT
BACKGROUND: We elucidated the effect of newly developed Fukuoka Apolipoprotein A-I Mimetic Peptide (FAMP) on in vivo macrophage reverse cholesterol transport (RCT) and the underlying mechanisms. METHODS AND RESULTS: Cholesteryl ester transfer protein transgenic mice were divided into FAMP, and placebo control groups, and injected with FAMP or phosphate buffer saline intraperitoneally for 5 days. The FAMP group showed a significant decrease in plasma high-density lipoprotein cholesterol (HDL-C), and plasma from the FAMP group had an increased ability to promote ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux from bone marrow macrophages ex vivo. Furthermore, mice were injected intraperitoneally with (3)H-cholesterol-labeled and cholesterol-loaded macrophages and monitored for the appearance of (3)H-tracer. The amount of (3)H-tracer excreted into feces over 48h in the FAMP group was significantly higher than that in the control group. (3)H-cholesterol ester (CE)-HDL was injected intravenously and (3)H-cholesterol in blood was counted. In the FAMP group, plasma (3)H-CE-HDL decreased rapidly, and treatment with FAMP markedly increased the fractional catabolic rate. CONCLUSIONS: The administration of FAMP promoted ABCA1-dependent efflux ex vivo, HDL turnover in vivo, and macrophage RCT in vivo despite reduced plasma HDL-C levels. FAMP might have atheroprotective potential.
Subject(s)
Apolipoprotein A-I/physiology , Cholesterol, HDL/metabolism , Macrophages/metabolism , ATP Binding Cassette Transporter 1/metabolism , Animals , Atherosclerosis/drug therapy , Biological Transport , Biomimetic Materials , Mice , Mice, TransgenicABSTRACT
BACKGROUND: It is not clear whether it is reasonable to use particular drugs for glycemic control in preference to other hypoglycemic agents in terms of the clinical outcome of percutaneous coronary intervention (PCI) in patients with diabetes mellitus (DM). METHODS AND RESULTS: Among 2148 patients (2568 lesions) in the FU-Registry, DM patients who underwent PCI (n=758; 922 lesions) were investigated to clarify the effects of various drugs for glycemic control on the clinical outcome [major adverse cardiac events (MACEs): death, myocardial infarction (MI), and target lesion revascularization (TLR)] over approximately 300 days of follow-up (UMIN000005679). The MACEs(+) group (n=165) had a higher usage of insulin (p<0.001) and a lower usage of biguanides (BG, p<0.05) and dipeptidyl peptidase-IV inhibitors (p<0.05) at PCI, compared to the MACEs(-) group (n=593). A multivariate logistic regression analysis showed that low-density lipoprotein cholesterol, insulin use, atherosclerosis obliterans, and lesion reference might be significantly associated with MACEs, while BG use was negatively correlated with MACEs (p=0.04). The cumulative frequency of MACEs in the insulin-treated group was significantly higher (p<0.05) than that in the non-insulin group, and the strongest association between insulin with MACEs was seen in the hemoglobin (Hb) A1c 6.5-7.5% group. There tended to be a negative correlation between the use of insulin and MACEs, with risk ratios of <1, for the HbA1c >8.5% groups. CONCLUSIONS: Among different hypoglycemic agents, treatment with insulin was associated with poor mid-term clinical outcomes in DM patients who underwent PCI, while BG use was negatively correlated with MACEs. It may be reasonable for patients with HbA1c >8.5% to avoid hyperglycemia and glucotoxicity, even through the use of insulin.
Subject(s)
Biguanides/therapeutic use , Diabetes Mellitus/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Myocardial Infarction/therapy , Percutaneous Coronary Intervention , Aged , Blood Glucose/metabolism , Diabetes Mellitus/blood , Female , Follow-Up Studies , Glycated Hemoglobin/metabolism , Humans , Incidence , Lipoproteins, LDL/blood , Male , Middle Aged , Myocardial Infarction/epidemiology , Registries , Regression Analysis , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Smoking cessation reduces the risk of cardiovascular disease (CVD) and improves clinical outcomes in public health. We studied the effect of smoking cessation on high-density lipoprotein (HDL) functionality. METHODSâANDâRESULTS: We randomly treated 32 smokers with varenicline or a transdermal nicotine patch as part of a 12-week smoking cessation program (The VN-SEESAW Study). The plasma lipid profiles, plasma and HDL malondialdehyde (MDA) levels, HDL subfractions as analyzed by capillary isotachophoresis, cholesterol efflux capacity, and antiinflammatory activity of HDL were measured before and after the anti-smoking intervention. After smoking cessation, HDL-C, apoA-I levels and HDL subfractions were not significantly different from the respective baseline values. However, cholesterol efflux capacity and the HDL inflammatory index (HII) were significantly improved after smoking cessation. The changes in both parameters (%∆ cholesterol efflux capacity and ∆HII) were also significantly improved in the successful smoking cessation group compared with the unsuccessful group. The changes in cholesterol efflux capacity and HII also correlated with those in end-expiratory CO concentration and MDA in HDL, respectively. CONCLUSIONS: Our findings indicate that smoking cessation leads to improved HDL functionality, increased cholesterol efflux capacity and decreased HII, without changing HDL-C or apoA-I levels or HDL subfractions. This may be one of the mechanisms by which smoking cessation improves the risk of CVD.
Subject(s)
Lipoproteins, HDL/blood , Smoking Cessation , Smoking/blood , 1-Alkyl-2-acetylglycerophosphocholine Esterase/blood , Administration, Cutaneous , Adult , Apolipoprotein A-I/blood , Benzazepines/therapeutic use , Cardiovascular Diseases/prevention & control , Cholesterol/metabolism , Cholesterol, HDL/blood , Cholinergic Agonists/therapeutic use , Female , Humans , Inflammation , Lipid Peroxidation/drug effects , Lipids/blood , Macrophages/metabolism , Male , Malondialdehyde/blood , Middle Aged , Nicotine/administration & dosage , Nicotine/therapeutic use , Oxidation-Reduction , Quinoxalines/therapeutic use , Receptors, Nicotinic , Risk Factors , VareniclineABSTRACT
BACKGROUND: There have been no previous reports that apolipoprotein (apo) A-I mimetic peptide improves survival rate after myocardial infarction (MI). METHOD AND RESULTS: Male C57Bl/6J mice were subjected to left coronary artery permanent ligation as a model of MI. We synthesized a novel 24-amino acid apoA-I mimetic peptide-type5 (FAMP5), which potently removes cholesterol via specific ATP-binding cassette transporter A1 (ABCA1). FAMP5 was associated with a significantly improved survival rate by protecting against cardiac rupture compared to the control. mRNA levels for eNOS, Gata-4, CTGF and ANP were significantly increased in the hearts of the FAMP5-treated group, while that for MCP-1 decreased. CONCLUSION: This is the first report that high-density lipoprotein (HDL) therapy with FAMP5 improved the survival rate after MI.