[Show abstract][Hide abstract] ABSTRACT: Abstract A positive association between inflammation and chronic kidney disease (CKD) has been reported but the impact of hypertension on this relation remains unclear. The aim of this study is to investigate the association of various inflammation markers with risk of CKD in hypertensive patients. 387 hypertensive patients (mean age 55.5 years) were recruited. Serum matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1(TIMP-1), high-sensitivity C-reactive protein (hsCRP) and osteopontin (OPN) were measured by ELISA. CKD was diagnosed either as evidence of kidney damage, including microalbuminuria, or by low glomerular filtration rate (GFR) (<60 mL/min/1.73 m(2)), which was estimated using the Modification of Diet in Renal Disease (MDRD) abbreviated equation. Compared with the reference groups (eGFR ≥ 60 mL/min/1.73 m(2)), the serum levels of TIMP-1, OPN, hsCRP were significantly higher, and the MMP-9/TIMP-1 ratio was lower in the risk group (eGFR < 60 mL/min/1.73 m(2)). Multiple logistic regression analysis showed that TIMP-1, MMP-9/TIMP-1 ratio, OPN and hsCRP were associated with low GFR separately after adjustment, whereas MMP-9/TIMP-1 ratio, OPN and hsCRP were associated with microalbuminuria. The significant association of MMP-9/TIMP-1 ratio and OPN with low GFR and microalbuminuria persisted after additional adjustment for other studied inflammatory biomarkers. Our data suggest that inflammation is strongly and independently associated with renal damage in hypertensive patients. MMP-9/TIMP-1 ratio and OPN may serve as novel risk factors and therapeutic targets for the treatment of CKD in hypertensive patients.
[Show abstract][Hide abstract] ABSTRACT: Hypertension is an important issue in Asia, responsible for up to 66% of cardiovascular disease cases. This randomized controlled trial subgroup analysis compared telmisartan 80 mg (T80)/hydrochlorothiazide 25 mg (H25) singlepill combination with T80 monotherapy, specifically in Chinese and Korean patients.
Patients with grade 2/3 hypertension were randomized to receive telmisartan 40 mg (T40)/hydrochlorothiazide 12.5 mg (H12.5) combination or T40 monotherapy for one week, before uptitrating the dose to T80/H25 or T80, respectively, for the remaining 6 weeks. The primary endpoint was systolic blood pressure (SBP) mean change from baseline. Secondary endpoints included mean diastolic blood pressure (DBP) change from baseline, and blood pressure (BP) goal achievement. Adverse events were recorded.
Of a total 888 patients who were treated, efficacy analyses for Chinese and Korean patients included 127 patients treated with T80/H25 and 54 patients treated with T80. At week 7, mean SBP reductions from baseline were -37.5 mmHg (1 mmHg = 0.133 kPa) and -26.9 mmHg in the T80/H25 and T80 groups (adjusted mean difference, -10.6 mmHg; 95% confidence interval (CI), -15.6 to -5.7). Mean DBP reductions were -19.0 and -14.1 mmHg in the T80/H25 and T80 groups (adjusted mean difference, -4.9 mmHg; 95% CI, -8.0 to -1.8). In total, 56.7% of patients receiving T80/H25 achieved BP goal (<140/90 mmHg) compared with 35.2% receiving T80. SBP goal attainment (<140 mmHg) and DBP goal attainment (<90 mmHg) were also higher in the T80/H25 group compared with the T80 group (SBP: 69.3% vs. 48.1%; DBP: 62.2% vs. 46.3%). A small number of treatment-related adverse events were observed in both T80/H25 (nine patients, 6.9%) and T80 monotherapy (two patients, 3.6%) groups.
In Chinese and Korean patients with moderate-to-severe hypertension, treatment with T80/H25 provided large reductions in mean SBP and DBP, and high BP goal attainment rates. This once-daily combination is effective and well tolerated in this patient group.
Chinese medical journal 11/2013; 126(21):4072-4077. · 1.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Angiotensin-converting enzyme 2 (ACE2) has been implicated in human heart failure, but the mechanism remains elusive. We hypothesized that ACE2 deficiency would exacerbate angiotensin (Ang) II-mediated myocardial injury. Methods and Results: 10-week-old ACE2 knockout (ACE2KO) and wild-type mice received by mini-osmotic pump either AngII (1.5mg·kg(-1)·day(-1)) or saline for 2 weeks. ACE2 deficiency triggered greater increases in the expression of connective tissue growth factor (CTGF), fractalkine (FKN) and phosphorylated ERK1/2 in AngII-treated ACE2KO hearts. These changes were associated with greater activation of matrix metalloproteinase (MMP) 2, MMP9 and MT1-MMP and exacerbation of myocardial injury and dysfunction. In cultured cardiofibroblasts, exposure to AngII (100nmol/L) for 30min resulted in marked increases in superoxide production and expression of CTGF, FKN and phosphorylated ERK1/2, which were strikingly prevented by recombinant human ACE2 (rhACE2; 1mg/ml) and the CTGF-neutralizing antibody (5μg/ml), but were aggravated by ACE2 inhibitor DX600 (0.5μmol/L). These protective effects of rhACE2 were eradicated by the Ang-(1-7) antagonist A779 (1μmol/L). More intriguingly, rhACE2 treatment significantly abolished AngII-mediated increases in MMP2, MMP9 and MT1-MMP in cardiofibroblasts. Conclusions: Loss of ACE2 exacerbates AngII-mediated inflammation, myocardial injury and dysfunction in ACE2-deficient hearts via activation of the CTGF-FKN-ERK and MMP signaling. ACE2 gene may represent a potential candidate to prevent and treat myocardial injury and heart diseases.
[Show abstract][Hide abstract] ABSTRACT: It is unclear at what time-window of the day blood pressure (BP) is most closely associated with cerebrovascular damage. In this cross-sectional study, we examined the strength of association between intracranial arterial stenosis (ICAS) and systolic BP (SBP) across different time-windows using 24-hour ambulatory BP monitoring in 757 consecutively recruited patients with hypertension. ICAS was diagnosed with computerized tomographic angiography in 127 (16.8%) patients, of whom 64 (50.4%) had stenosis ≥50% and 82 (64.6%) had ICAS in ≥2 vessels. Patients with ICAS (142 mm Hg), especially of multiple vessels (145 mm Hg), compared with patients without ICAS (126 mm Hg), had significantly (P<0.001) higher early morning (05:00-07:59 am) SBP. The differences remained significant (P≤0.015) after adjustment for cardiovascular risk factors and SBPs at other time-windows of the day. Multivariate regression analysis showed that consecutive 3-hourly mean SBPs during the day were significantly associated with ICAS (odds ratio for each 10-mm Hg increase, 1.28-1.38; P≤0.001). However, only mean SBP obtained between 05:00 am and 07:59 am remained significant for ICAS (odds ratio, 1.30; P=0.019) when all consecutive 3-hourly mean SBPs were forced into a single multivariate model. In conclusion, the present study showed a significant association between early morning SBP and asymptomatic ICAS in patients with hypertension after accounting for conventional cardiovascular risk factors. Our findings highlight the importance of morning SBP as a cardiovascular risk factor and should be validated in prospective studies.
[Show abstract][Hide abstract] ABSTRACT: Angiotensin-converting enzyme 2 (ACE2), a monocarboxypeptidase which metabolizes angiotensin II (Ang II) to generate Ang-(1--7), has been shown to prevent cardiac hypertrophy and injury but the mechanism remains elusive. Irbesartan has the dual actions of angiotensin receptor blockade and peroxisome proliferator-activated receptor-gamma (PPARgamma) activation. We hypothesized that irbesartan would exert its protective effects on ACE2 deficiency-mediated myocardial fibrosis and cardiac injury via the PPARgamma signaling.
10-week-old ACE2 knockout (ACE2KO; Ace2-/y) mice received daily with irbesartan (50 mg/kg) or saline for 2 weeks. The wild-type mice (Ace2+/y) were used to the normal controls. We examined changes in myocardial ultrastructure, fibrosis-related genes and pathological signaling by real-time PCR gene array, Western blotting, Masson trichrome staining and transmission electron microscope analyses, respectively.
Compared with the Ace2+/y mice, cardiac expression of PPARalpha and PPARgamma were reduced in Ace2-/y mice and the myocardial collagen volume fraction (CVF) and expression of fibrosis-related genes were increased, including transforming growth factor-beta1 (TGFbeta1), connective tissue growth factor (CTGF), collagen I and collagen III. Moreover, ACE2 deficiency triggered cardiac hypertrophy, increased myocardial fibrosis and adverse ultrastructure injury in ACE2KO hearts with higher levels of atrial natriuretic factor (ANF) and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), without affecting cardiac systolic function. Intriguingly, treatment with irbesartan significantly reversed ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in Ace2-/y mice linked with enhancement of plasma Ang-(1--7) level and downregulation of AT1 receptor in heart. Consistent with attenuation of myocardial fibrosis and ultrastructure injury, the myocardial CVF and levels of ANF, TGFbeta1, CTGF, collagen I, collagen III and phosphorylated ERK1/2 were lower, and expression of PPARgamma was higher in ACE2KO mice in response to irbesartan treatment, without affecting cardiac expression of PPARalpha, PPARdelta, beta-myosin heavy chain, TGFbeta2 and fibronectin.
We conclude that irbesartan prevents ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in ACE2 mutant mice via activation of the PPARgamma signaling and suppression of the TGFbeta-CTGF-ERK signaling, resulting in attenuation of myocardial injury. Drugs targeting ACE2 and PPARgamma represent potential candidates to prevent and treat myocardial injury and related cardiac disorders.
Journal of Translational Medicine 09/2013; 11(1):229. DOI:10.1186/1479-5876-11-229 · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: β-blockers (BBs) with different pharmacological properties may have heterogeneous effects on sympathetic nervous activity (SNA) and central aortic pressure (CAP), which are independent cardiovascular factors for hypertension. Hence, we analyzed the effects of bisoprolol and atenolol on SNA and CAP in hypertensive patients.
This was a prospective, randomized, controlled study in 109 never-treated hypertensive subjects randomized to bisoprolol (5 mg) or atenolol (50 mg) for 4-8 weeks. SNA, baroreflex sensitivity (BRS) and heart rate (HR) variability (HRV) were measured using power spectral analysis using a Finometer. CAP and related parameters were determined using the SphygmoCor device (pulse wave analysis).
Both drugs were similarly effective in reducing brachial BP. However, central systolic BP (-14±10 mm Hg vs -6±9 mm Hg; P<0.001) and aortic pulse pressure (-3±10 mm Hg vs +3±8 mm Hg; P<0.001) decreased more significantly with bisoprolol than with atenolol. The augmentation index at a HR of 75 bpm (AIxatHR75) was significantly decreased (29%±11% to 25%±12%; P = 0.026) in the bisoprolol group only. Furthermore, the change in BRS in the bisoprolol group (3.99±4.19 ms/mmHg) was higher than in the atenolol group (2.66±3.78 ms/mmHg), although not statistically significant (P>0.05). BRS was stable when RHR was controlled (RHR≤65 bpm), and the two treatments had similar effects on the low frequency/high frequency (HF) ratio and on HF.
BBs seem to have different effects on arterial distensibility and compliance in hypertensive subjects. Compared with atenolol, bisoprolol may have a better effect on CAP.
PLoS ONE 09/2013; 8(9):e72102. DOI:10.1371/journal.pone.0072102 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the association of left ventricular (LV) diastolic function and N-terminal pro-brain natriuretic peptide (NT-proBNP) with renal function in essential hypertension.
LV diastolic function was estimated by the ratio of early diastolic velocities (E) from transmitral inflow to early diastolic velocities (E') of tissue Doppler at mitral annulus (septal corner); NT-proBNP was measured in 207 hypertensive patients (mean age 56±14 years). The subjects were classified into 3 groups: E/E'≤10 group (n = 48), 10<E/E'≤15 group (n = 109) and E/E'>15 group (n = 50). The renal function was estimated by glomerular filtration rate (GFR) with (99m)Tc-DTPA. GFR from 30 to 59 ml/min/1.73 m(2) was defined as Stage 3 chronic kidney disease (CKD). GFR was also estimated using the modified MDRD equation. Albuminuria was defined by urinary albumin/creatinine ratio (UACR).
GFR was lower and UACR was higher in E/E' >15 group than in 10< E/E' ≤15 group or E/E' ≤10 group (p<0.0001), GFR was significantly negative and UACR was positive correlated with E/E' and NT-proBNP (p<0.0001). In multivariate stepwise linear analysis, GFR had significant correlation with age (p = 0.001), gender (p = 0.003), E/E' (p = 0.03), lgNT-proBNP (p = 0.001) and lgUACR (p = 0.01), while eGFR had no significant correlation with E/E' or lgNT-proBNP. Multivariate logistic regression analysis, adjusted for potential confounding factors, showed that participants in E/E'>15 group were more likely to have Stage 3 CKD compared with those in E/E'≤10 group with an adjusted odds ratio of 8.31 (p = 0.0036).
LV diastolic function, assessed with E/E' and NT-proBNP is associated with renal function in essential hypertension.
PLoS ONE 01/2013; 8(1):e54513. DOI:10.1371/journal.pone.0054513 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim:
To investigate whether apocynin, a NADPH oxidase inhibitor, produced cardioproteictive effects in Ang II-induced hypertensive mice, and to elucidate the underlying mechanisms.
C57BL/6 mice were subcutaneously infused Ang II for 4 weeks to mimic cardiac remodeling and fibrosis. Concomitantly the mice were administered apocynin (100 mg·kg−1·d−1) or/and the aldosterone receptor blocker eplerenone (200 mg·kg−1·d−1) via gavage for 4 weeks. Systolic blood pressure (SBP) and heart rate were measured, and transthoracic echocardiography was performed. For in vitro study, cardiac fibroblasts were treated with Ang II (10−7 mol/L) in the presence of apocynin (10−5 mol/L) or/and eplerenone (10−5 mol/L). Immunohistochemistry and Western blotting were used to quantify the expression levels of NADPH oxidase and osteopontin (OPN) proteins in the cells.
Both apocynin and eplerenone significantly decreased SBP, and markedly improved diastolic dysfunction in Ang II-induced hypertensive mice, accompanied with ameliorated oxidative stress and cardiac fibrosis. In the Ang II-treated cardiac fibroblasts, the expression levels of NOX4 and OPN proteins were markedly upregulated. Both Apocynin and eplerenone significantly suppressed the increased expression levels of NOX4 and OPN proteins in the Ang II-treated cells. In all the experiments, apocynin and eplerenone produced comparable effects. Co-administration of the two agents did not produce synergic effects.
Apocynin produces cardioproteictive effects comparable to those of eplerenone. The beneficial effects of apocynin on myocardial oxidative stress and cardiac fibrosis might be mediated partly through a pathway involving NADPH oxidase and OPN.
[Show abstract][Hide abstract] ABSTRACT: This study sought to determine if apocynin, a nicotinamide adenine dinucleotide phosphate oxidase inhibitor, would attenuate arterial stiffness in salt-sensitive hypertensive rats via structural and functional changes in conduit arteries. We showed that tail blood pressure was significantly higher in deoxycorticosterone acetate-salt-induced hypertensive (DSH) rats compared with the sham control group (P<0.01). Morphological analysis and biochemical assay showed that large arteries in DSH rats underwent significant remodeling including increased medial thickness in carotid arteries compared with the control rats (194.25±5.66 vs. 120.48±7.93 μm, P<0.05) and increased collagen deposition in thoracic aorta (1.03±0.09 vs. 0.85±0.04 mg cm(-1), P<0.05). These changes were associated with increases in reactive oxygen species (ROS) level and increased thoracic aortic stiffness compared with the control rats (6.21±0.79 m s(-1) vs. 4.64±0.59 m s(-1), P<0.01). Treatment with apocynin significantly prevented ROS increases and collagen deposition (0.84±0.04 vs. 1.03±0.09 mg cm(-1), P<0.05), and reduced arterial stiffness as shown by decreased pulse wave velocity in the thoracic aorta (5.31±0.88 vs. 6.21±0.79 m s(-1), P<0.01). Additionally, apocynin prevented carotid artery wall thickening (58.57±3.40 vs. 78.89±4.10 μm, P<0.05). In conclusion we have shown that increased ROS level is associated with increased aortic stiffness, and deposition of collagen in the aortic arterial wall in DSH rats. Apocynin prevented ROS increases and arterial stiffness in DSH rats. Antioxidant therapy may be a potential treatment of large arterial stiffness in salt-sensitive hypertension.Hypertension Research advance online publication, 15 November 2012; doi:10.1038/hr.2012.170.
Hypertension Research 11/2012; 36(4). DOI:10.1038/hr.2012.170 · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives: We hypothesized that angiotensin-converting enzyme 2 (ACE2) deficiency would facilitate angiotensin (Ang) II-mediated vascular inflammation and the actin-binding protein profilin-1 signaling. Design and methods: We randomized 10-week ACE2 knockout (ACE2KO, Ace2-/y) and wild-type littermates (WT, Ace2+/y) mice to Ang II (1.5 mg.kg-1.d-1) infusion with mini-osmotic pumps and treated daily with irbesartan (50 mg/kg) for 2 weeks. Results: Aortic ACE2 protein was obviously reduced in WT mice in response to Ang II related to increases in profilin-1 protein. Loss of ACE2 resulted in greater increases in Ang II-induced mRNA expressions of inflammatory cytokines MCP-1, IL-1[beta], and IL-6 in aortas of ACE2KO mice, along with enhanced profilin-1 expression and phosphorylated ERK1/2 levels. Interestingly, irbesartan significantly attenuated Ang II-mediated aortic inflammation in WT mice with enhanced ACE2 levels and suppression of the profilin-1/ERK signaling. Conclusions: Our findings reveal that ACE2 deficiency worsens Ang II-mediated aortic inflammation and profilin-1 signaling, suggesting a potential therapeutic approach by enhancing ACE2 action for patients with vascular diseases. Supported by National Natural Science Foundation of China (30973522&81170246), Shanghai Pujiang Talents Program (11PJ1408300), and CIHR (86602&84279).
Journal of Hypertension 09/2012; 30:e303. DOI:10.1097/01.hjh.0000420984.25019.c2 · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adventitia acts as an active participant in vascular inflammation but the precise mechanism underlying adventitia-mediated vascular inflammation is not fully understood. In this study, we sought to determine whether vascular endothelial growth factor (VEGF) regulates osteopontin (OPN) expression through Flt-1 in adventitial fibroblasts (AFs) to mediate vascular inflammation and neointima formation.
In primary cultured AFs, VEGF increased intracellular and secreted OPN expression in a time- and dose-dependent manner, which was effectively suppressed by a specific anti-Flt-1 hexapeptide. Interestingly, VEGF treatment of AFs enhanced the capability of AF-conditioned medium to stimulate macrophages chemotaxis, and this effect was attenuated after blockade of OPN from AF-conditioned medium. Furthermore, perivascular delivery of anti-Flt-1 peptide preferentially concentrated in the adventitia resulted in a decrease of neointima formation after balloon injury in carotid arteries. The inhibition of neointima formation was preceded by significant reduction of VEGF and OPN expression with concurrent macrophage infiltration into adventitia after injury. Activation of extracellular signal-regulated kinase 1/2 pathway was involved in OPN upregulation and macrophage chemotaxis.
These results demonstrate that VEGF/Flt-1 signaling plays a significant role in vascular inflammation and neointima formation by regulating OPN expression in AFs and provide insight into Flt-1 as a potential therapeutic target for vascular diseases.
[Show abstract][Hide abstract] ABSTRACT: C-reactive protein (CRP), an acute phase reactant and marker of inflammation, has been shown to be associated with CRP genetic variants and incident hypertension, but it is unclear whether this link is causal. We therefore conducted a prospective, nested case-control study to examine the relationship between single-nucleotide polymorphisms (SNPs) within the CRP gene, circulating CRP levels and the development of hypertension. Plasma CRP levels and the genotypes of eight SNPs were determined in 2000 unrelated Shanghai residents, including 908 hypertensive individuals and 1092 normotensive individuals. Among the 1092 normotensives, 968 subjects were followed up for 2 years, during which 71 developed hypertension. Plasma CRP levels were independently associated with the development of hypertension in the follow-up study (odds ratio per quartile=1.64; 95% confidence interval: 1.18-2.26; P<0.001). The minor alleles of rs1130864 (P<0.001) and rs3093059 (P<0.001) were significantly associated with elevated CRP levels, and the minor alleles of rs1205, rs1800947 and rs2246469 (all P<0.001) were associated with decreased CRP levels. A haplotype-based analysis strengthened the results of single-locus analysis. However, none of the SNPs or haplotypes was significantly associated with blood pressure, incident hypertension or changes between baseline and follow-up blood pressure levels. Taken together, our findings demonstrated that plasma CRP levels were substantially associated with common genetic variants in the CRP gene and could predict the development of hypertension. However, the relationship between genotype and CRP levels was not associated with a change in hypertension risk.
Hypertension Research 07/2012; 35(10):1019-23. DOI:10.1038/hr.2012.89 · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inflammation and oxidative stress play a crucial role in angiotensin (Ang) II-mediated vascular injury. Angiotensin-converting enzyme 2 (ACE2) has recently been identified as a specific Ang II-degrading enzyme but its role in vascular biology remains elusive. We hypothesized that loss of ACE2 would facilitate Ang II-mediated vascular inflammation and peroxynitrite production. 10-week wildtype (WT, Ace2(+/y)) and ACE2 knockout (ACE2KO, Ace2(-/y)) mice received with mini-osmotic pumps with Ang II (1.5 mg.kg⁻¹.d⁻¹) or saline for 2 weeks. Aortic ACE2 protein was obviously reduced in WT mice in response to Ang II related to increases in profilin-1 protein and plasma levels of Ang II and Ang-(1-7). Loss of ACE2 resulted in greater increases in Ang II-induced mRNA expressions of inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1β, and IL-6 without affecting tumor necrosis factor-α in aortas of ACE2KO mice. Furthermore, ACE2 deficiency led to greater increases in Ang II-mediated profilin-1 expression, NADPH oxidase activity, and superoxide and peroxynitrite production in the aortas of ACE2KO mice associated with enhanced phosphorylated levels of Akt, p70S6 kinase, extracellular signal-regulated kinases (ERK1/2) and endothelial nitric oxide synthase (eNOS). Interestingly, daily treatment with AT1 receptor blocker irbesartan (50 mg/kg) significantly prevented Ang II-mediated aortic profilin-1 expression, inflammation, and peroxynitrite production in WT mice with enhanced ACE2 levels and the suppression of the Akt-ERK-eNOS signaling pathways. Our findings reveal that ACE2 deficiency worsens Ang II-mediated aortic inflammation and peroxynitrite production associated with the augmentation of profilin-1 expression and the activation of the Akt-ERK-eNOS signaling, suggesting potential therapeutic approaches by enhancing ACE2 action for patients with vascular diseases.
PLoS ONE 06/2012; 7(6):e38502. DOI:10.1371/journal.pone.0038502 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteopontin (OPN) is known to be one of the cytokines that is involved in the vascular inflammation caused by aldosterone (Ald). Previous reports have shown that Ald increases OPN expression, and the mechanisms for this remain to be clarified. In this study, we investigated how Ald increases OPN expression in the vascular smooth muscle cells (VSMCs) of rats. Ald increased OPN expression time dependently as well as dose dependently. This increase was diminished by spironolactone, a mineralocorticoid receptor (MR) antagonist. PD98059, an inhibitor of p42/44 MAPK pathway, and SB203580, an inhibitor of p38 MAPK pathway, suppressed Ald-induced OPN expression and secretion in VSMCs. VSMCs migration stimulated by aldosterone required OPN expression. In conclusion, these data suggest that Ald-induced OPN expression in VSMC is mediated by MR and signaling cascades involving ERK and p38 MAPK. These molecules may represent therapeutic targets for the prevention of pathological vascular remodeling.
[Show abstract][Hide abstract] ABSTRACT: Osteopontin is known to play important roles in various diseases including vascular disorders. However, little is known about its expression and function in vascular adventitial fibroblasts. Adventitial fibroblasts have been shown to play a key role in pathological vascular remodeling associating with various vascular disorders. In this study, we measured activation of Osteopontin and its biological functions in cultured adventitial fibroblasts and injured rat carotid injury arteries induced by balloon angioplasty. Our results showed that angiotensin II and aldosterone increased Osteopontin expression in adventitial fibroblasts in a time- and concentration-dependent manner. MAPKs and AP-1 pathways were involved in Osteopontin upregulation. In addition, Adventitial fibroblast migration stimulated by Angiotensin II and aldosterone required OPN expression. Perivascular delivery of antisense oligonucleotide for Osteopontin suppressed neointimal formation post-injury. We concluded that upregulation of Osteopontin expression in adventitial fibroblasts might be important in the pathogenesis of vascular remodeling after arterial injury.
PLoS ONE 10/2011; 6(9):e23558. DOI:10.1371/journal.pone.0023558 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The ambulatory arterial stiffness index (AASI) predicted stroke in hypertensive patients and in the general populations. However, no similar data was available in Chinese. In the present study, we sought confirmation that Chinese hypertensive patients with a history of stroke would have an elevated AASI. We retrospectively analyzed the data of 156 hypertensive outpatients (60.9 % men; mean age, 61.5 years) and 582 inpatients (63.6 % men; 58.6 years) of the Hypertension Department at Ruijin Hospital in Shanghai, China. The AASI was calculated as 1 - the regression slope of diastolic blood pressure (DBP) on systolic blood pressure (SBP) in individual 24-h ambulatory recordings. With adjustment applied for sex, age, body mass index (BMI), the 24-h mean arterial pressure, and other cardiovascular risk factors, AASI was higher in patients with a history of stroke than in patients without stroke in both outpatient (0.51 ± 0.02 vs. 0.47 ± 0.01; P = 0.050) and inpatient (0.46 ± 0.01 vs. 0.44 ± 0.01; P = 0.031) cohorts. The odds ratio (OR) for a history of stroke associated with a 1-SD increase in AASI was 1.63 (95% confidence interval (CI), 1.01-2.62; P = 0.046) in outpatients, 1.32 (1.01-1.74; P = 0.046) in inpatients, and 1.30 (1.05-1.62; P = 0.018) in two patient cohorts combined (n = 738) after multivariate adjustment including the night-to-day ratio of SBP. Our findings suggest that Chinese hypertensive patients with a history of stroke, compared to those without such history, have stiffer arteries, as exemplified by a higher AASI.