Intelligent Assist Office Blood Pressures (IOBP) versus awake ambulatory monitoring and conventional auscultatory office readings in Chinese primary medical institutions.

To practice standardized office blood pressure (OBP) measurement guidelines pragmatically, we developed an intelligent assisted OBP (IOBP) measurement system in the Chinese community, which can automatically obtain two or three BP values after a 5-min rest before the patients visit the doctor and transfer values to the community medical network in real time. We conducted a comparative study to investigate the agreement among IOBP, awake ambulatory BP (ABP), and conventional auscultatory OBP at different BP levels. Participants were divided into three groups according to BP, with 120/80 mmHg and 160/100 mmHg as the cut-off points. Attended IOBP, unattended IOBP, and auscultatory OBP were randomly measured before ABP monitoring. In total, 245 participants were included in the analysis. The mean systolic attended/unattended IOBP, auscultatory OBP, and awake ABP were 135.0, 136.7, 135.6, and 136.2 mmHg, respectively. Bland-Altman analysis revealed a bias of -1.1 and 0.5 mmHg for systolic attended/unattended IOBP compared with awake ABP in the overall sample. For auscultatory OBP, the bias was -0.4 (attended) and 1.2 mmHg (unattended). The discrepancy between the systolic attended/unattended IOBP and awake ABP was inconsistent at different BP levels. In Group 1 the values were -8.4 and -6.9 mmHg, whereas in Group 3, the values were 9.4 and 10.0 mmHg. BP measured using the IOBP measurement system was in accordance with awake ABP and conventional OBP, and can be a good choice in the Chinese community.

Genome-wide analysis of DNA methylation and its relationship with serum homocysteine levels in patients with hypertension.

BACKGROUND: Homocysteine (Hcy) is an independent risk factor for cardiovascular diseases, and elevated plasma Hcy levels could aggravate vascular injury in hypertension. Hyperhomocysteinemia can change the methylation status of global DNA and specific genes. In the present study, we aim to examine the comprehensive influence of Hcy levels on DNA methylation status in patients with hypertension. METHODS: Epigenome-wide methylation profiles of the peripheral leukocyte DNA of 218 patients with hypertension were analyzed using the Illumina Infinium Methylation EPIC BeadChip. Differentially methylated positions (DMPs) associated with serum Hcy levels were identified by mixed linear regression with the adjustment of potential confounders. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted to determine the potential functions of the identified DMPs. The association between the methylation level of DMPs and carotid-femoral pulse wave velocity (Cf-PWV) was also analyzed. RESULTS: Five DMPs at cg13169662, cg03179312, cg21976560, cg25262698, and cg09433843 showed significant association with serum Hcy levels (false discovery rate-corrected P  < 0.05). An additional six CpG sites met the threshold for suggestive significance ( P  < 1 × 10 -6 ), among which three DMPs (cg25781123, cg26463106, and cg06679221) were annotated to THUMPD3 . Furthermore, the methylation levels of cg13169662 and cg25262698 (RPRD1A) were significantly associated with Cf-PWV. CONCLUSION: Our results suggest that Hcy could induce DNA methylation alteration in patients with hypertension. Further functional research is warranted to elucidate the concrete role of DMPs in hypertension.

Prevalence of hyperhomocysteinemia (HHcy) and its major determinants among hypertensive patients over 35 years of age.

OBJECTIVE: Hyperhomocysteinemia (HHcy) and hypertension are associated with cardiovascular events. However, effects of Hcy-lowing interventions on cardiovascular outcome were conflicting. Serum folate level was proposed to be a possible determinant of efficacy of extra folate supplementation on cardiovascular outcome. The aims of the present study were to describe representative information on the levels of serum homocysteine and folate in hypertensive patients, and to explore the major determinants of HHcy. METHODS: 11,007 participants with hypertension were analyzed in this cross-sectional study. Blood pressure and serum levels of biochemical indicators were measured. Multivariate logistic regression model was used to assess the associated factors of HHcy. RESULTS: Geometric mean of serum total homocysteine was 14.1 (95% CI: 13.9, 14.4) µmol/L and prevalence of HHcy was 36.1 (95% CI: 34.0, 38.1) % in hypertensive patients. HHcy was strongly associated with factors including male sex, older age, elevated serum creatinine (SCr), lower serum folate and vitamin B12, and uncontrolled blood pressure in hypertensive patients. Elevated SCr attributed to HHcy with the etiologic fraction of 0.29. The change of the odds ratio of HHcy associated with folate was significantly higher in patients with elevated SCr compared with that of patients with normal SCr. CONCLUSION: The results suggested the protection of female sex and higher levels of folate and vitamin B12 from HHcy and attribution of older age and elevated SCr to HHcy. Restoring renal function deserved attention for hypertensive patients to benefit from Hcy-lowing measures.

Predictive value of attended automated office blood pressure and resting pulse rate for mortality in community-dwelling octogenarians: Minhang study.

Systolic blood pressure (SBP) and resting pulse rate (RPR) have been linked to mortality and cardiovascular events in younger population. Till now, no studies simultaneously investigate the non-linear association of SBP and RPR with all-cause and cardiovascular mortality among population aged 80 and older. Data of 2828 eligible participants were selected from electronic health records linked attended automated office blood pressure measurement system. The dose-response relationship between the SBP, RPR, and the risk of all-cause and cardiovascular mortality was analyzed by Cox model with restricted cubic splines. During the 3.6-year follow-up, 442 deaths occurred. Comparing with the optimal SBP (117-145 mmHg), the lower (HR: 1.39, 95% CI: 1.07-1.81) and higher SBP (HR: 1.34, 95% CI: 1.08-1.65) were significantly associated with an increasing risk of all-cause mortality. The higher SBP (>144 mmHg) was associated with cardiovascular mortality, with the HR (95% CI) as 1.51 (1.07-2.12). The faster RPR showed the higher risk of all-cause (HR: 1.36, 95% CI: 1.05-1.76) and cardiovascular (HR: 1.51, 95% CI: 1.07-2.13) mortality. We found both higher SBP and faster RPR were independently associated with all-cause and cardiovascular mortality, and lower SBP was only associated with the increased risk of all-cause mortality in oldest old community-dwelling Chinese population. Our results demonstrate the prognostic importance of both SBP and RPR in the elderly.

Predictive value of within-visit and visit-to-visit blood pressure variability for all-cause mortality: the Minhang Study.

BACKGROUND: Blood pressure variability is a common physiological phenomenon; however, the association between within-visit and visit-to-visit variability in blood pressure and all-cause mortality remains uncertain. METHODS: We conducted a retrospective analysis of blood pressure variability among 11 721 adults who underwent blood pressure measurement on three occasions within a period of 6 months. Within-visit and visit-to-visit variability was quantified using the standard deviation and maximum--minimum difference between measures. The predictive effect of this variability on all-cause mortality was evaluated using Kaplan--Meier survival curves and Cox regression analysis. RESULTS: The incidence of all-cause mortality was significantly higher for participants in the top quintile of within-visit and visit-to-visit blood pressure variability and for those with sustained high within-visit variability. Within-visit variability was not retained as a risk factor after adjustment in Cox regression models. The hazard ratio for mortality increased from 48 to 55% for the top quintile of visit-to-visit blood pressure variability and from 56 to 61% for sustained high within-visit variability. The risk of mortality remained statistically higher even if visit-to-visit blood pressure variability was added to the model, including consistency of within-visit blood pressure variability and vice versa. CONCLUSION: Visit-to-visit and sustained high within-visit blood pressure variability were significant positive prognostic factors for all-cause mortality. Our findings underlined the clinical significance of achieving stable blood pressure in an effective plan of hypertension management.

Transient Receptor Potential Melastatin 7 Promotes Vascular Adventitial Fibroblasts Phenotypic Transformation and Inflammatory Reaction Induced by Mechanical Stretching Stress via p38 MAPK/JNK Pathway.

Remodeling of the arteries is one of the pathological bases of hypertension. We have previously shown that transient receptor potential melastatin 7 (TRPM7) aggravates the vascular adventitial remodeling caused by pressure overload in the transverse aortic constriction (TAC) model. In this study, we sought to explore the functional expression and downstream signaling of TRPM7 in vascular adventitial fibroblasts (AFs) stimulated by mechanical stretching stress (MSS). The expression of TRPM7 was upregulated with a concomitant translocation to the cytoplasm in the AFs stimulated with 20% MSS. Meanwhile, the expression of α-smooth muscle actin (α-SMA), a marker of transformation from AFs to myofibroblasts (MFs) was also increased. Moreover, AF-conditioned medium caused a significant migration of macrophages after treatment with MSS and contained high levels of monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). Pharmacological and RNA interference approaches using the TRPM7 inhibitor 2-aminoethoxydiphenyl borate (2-APB) and specific anti-TRPM7 small interfering RNA (si-RNA-TRPM7) abrogated these changes significantly. Further exploration uncloaked that inhibition of TRPM7 reduced the phosphorylation of p38 MAP kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) in the AFs stimulated with MSS. Furthermore, inhibition of the phosphorylation of p38MAPK or JNK could also alleviate the MSS-induced expression of α-SMA and secretion of inflammatory factors. These observations indicate that activated TRPM7 participates in the phenotypic transformation and inflammatory action of AFs in response to MSS through the p38MAPK/JNK pathway and suggest that TRPM7 may be a potential therapeutic target for vascular remodeling caused by hemodynamic changes in hypertension.

Associations between various attended automated office blood pressure estimations and all-cause and cardiovascular mortality: Minhang study.

BACKGROUND: The method of evaluating office blood pressure (OBP) varies greatly among different guidelines. OBJECTIVES: We performed a cohort study to compare the association of various directly transferred attended automated OBP (AOBP) estimations with all-cause and cardiovascular mortalities. METHODS: Overall, 475 181 sets of OBPs from 35 622 participants aged 35 years or older were extracted from the electronic health record of the Xinzhuang town hospital in the Minhang District, Shanghai, China. Each set of OBPs contained three consecutive AOBPs that were transferred directly to the electronic health record. The mean of three OBPs, mean of the last two OBPs, and alternative average OBP were calculated. RESULTS: The difference between the first and average OBPs changed along with the calendar month, and it was highest in December (5.3/2.1 mmHg) and lowest in July (3.8/2.0 mmHg). The subjects older than 80 years of age displayed the largest discrepancy in the blood pressure control rate according to the first OBP or average OBP (12.1%). During the 3.9-year follow-up, 1055 deaths occurred. The alternative average SBP was associated with both all-cause [hazard ratio: 1.07, 95% confidence interval (CI): 1.04-1.11] and cardiovascular (hazard ratio: 1.17, 95% CI: 1.11-1.23) mortalities. The uncontrolled alternative average OBP remained significantly associated with an increasing risk of all-cause (hazard ratio: 1.24, 95% CI: 1.09-1.40) and cardiovascular (hazard ratio: 1.53, 95% CI: 1.25-1.86) mortality, but not the average of the last two or mean of three readings. CONCLUSION: We observed an obvious discrepancy in the OBP level and OBP control rate according to different AOBP estimations. The alternative average OBP seemed to be more powerful in predicting both all-cause and cardiovascular mortalities than the average of the last two or mean of three readings.

Adventitial fibroblast-derived vascular endothelial growth factor promotes vasa vasorum-associated neointima formation and macrophage recruitment.

AIMS: Adventitial vasa vasorum provides oxygen and nourishment to the vascular wall, but whether it regulates vascular disease remains unclear. We have previously shown that an increased expression of VEGF (vascular endothelial growth factor) is associated with macrophage infiltration. This study aims to determine whether adventitial fibroblast (AF)-derived VEGF increases the number of vasa vasorum contributing to neointima formation through macrophage recruitment. METHODS AND RESULTS: In rat balloon injury model, vasa vasorum count was increased particularly in the adventitia accompanied by cell proliferation and VEGF expression. Both endogenous and PKH26-labelled exogenous macrophages were mainly distributed in adventitia around vasa vasorum. Interestingly, perivascular delivery of Ranibizumab preferentially concentrated in adventitia resulted in a decrease of neointima formation with concurrent reduction of vasa vasorum count and macrophage infiltration. AFs with adenovirus-mediated VEGF over-expression delivered to the adventitia significantly enhanced these pathological changes after injury. In Tie2-cre/Rosa-LoxP-RFP mice, endothelial cells were increased in the adventitia after wire injury. By using multiphoton laser scanning microscopy, macrophage rolling, adhesion and transmigration were observed in vasa vasorum. Moreover, adoptive transfer of macrophages accelerated injury-induced neointima formation. VEGF-neutralizing antibody administration also attenuated wire injury-induced neointima formation and macrophage infiltration. In primary cultured AFs, exogenous VEGF increased VEGF expression and secretion in a time- and dose-dependent manner. AF-conditioned medium promoted endothelial cell angiogenesis, vascular cell adhesion molecule-1 expression and macrophage adhesion was blocked by VEGF-neutralizing antibody and VEGFR2 inhibitor ZM323881, which also inhibited activation of VEGFR2/ERK1/2 pathway. CONCLUSION: These results demonstrate that AF-derived VEGF plays a significant role in the increase of vasa vasorum count which is involved in macrophage recruitment and neointima formation.

Perivascular adipose tissue-derived stromal cells contribute to vascular remodeling during aging.

Aging is an independent risk factor for vascular diseases. Perivascular adipose tissue (PVAT), an active component of the vasculature, contributes to vascular dysfunction during aging. Identification of underlying cell types and their changes during aging may provide meaningful insights regarding the clinical relevance of aging-related vascular diseases. Here, we take advantage of single-cell RNA sequence to characterize the resident stromal cells in the PVAT (PVASCs) and identified different clusters between young and aged PVASCs. Bioinformatics analysis revealed decreased endothelial and brown adipogenic differentiation capacities of PVASCs during aging, which contributed to neointimal hyperplasia after perivascular delivery to ligated carotid arteries. Mechanistically, in vitro and in vivo studies both suggested that aging-induced loss of peroxisome proliferator-activated receptor-γ coactivator-1 α (PGC1α) was a key regulator of decreased brown adipogenic differentiation in senescent PVASCs. We further demonstrated the existence of human PVASCs (hPVASCs) and overexpression of PGC1α improved hPVASC delivery-induced vascular remodeling. Our finding emphasizes that differentiation capacities of PVASCs alter during aging and loss of PGC1α in aged PVASCs contributes to vascular remodeling via decreased brown adipogenic differentiation.

Urine albumin-to-creatinine ratio and asymptomatic intracranial atherosclerotic stenosis in hypertensive patients.

Intracranial atherosclerotic stenosis (ICAS) contributes to nearly 50% of stroke in China, especially in patients with hypertension. Urine albumin-to-creatinine ratio (ACR) has been related to stroke and other atherosclerotic cardiovascular diseases. However, there is limited information about the association of ACR and early impairment of cerebral vessels. Hereby we assessed the association of ICAS with ACR, estimated glomerular filtration rate (eGFR), and dipstick proteinuria in a stroke-free hypertensive population. We included 889 hypertension patients aged ≥60 years without prior stroke. Computed tomography angiography was performed to detect ICAS. ACR and dipstick proteinuria were tested from a random spot urine. eGFR was calculated using the CKD-EPI equation. Logistic regression was carried out to analyze the association of renal function with the presence, extent, and lesion number of ICAS. Elevated ACR (≥30 mg/g) was associated with ICAS after adjustment of confounding factors (odds ratio (OR) = 1.66, 95% confidence interval (CI): 1.21-2.29). Patients with elevated ACR were more prone to develop moderate-to-severe stenosis (OR = 1.57, 95% CI: 1.16-2.14) and more lesions (OR = 1.58, 95% CI: 1.16-2.15). Such association was independent of previously identified cardiovascular risk factors. No significant association was detected between ICAS and dipstick proteinuria or eGFR after adjustment. Our findings suggested that elevated ACR was associated with asymptomatic ICAS in an aged stroke-free hypertensive population.

Transactivation domain of Krüppel-like factor 15 negatively regulates angiotensin II-induced adventitial inflammation and fibrosis.

Krüppel-like factor (KLF) 15 has emerged as a critical regulator of fibrosis in cardiovascular diseases. However, the precise role that KLF15 and its functional domain played in adventitial inflammation and fibrosis remains unclear. This study aims to investigate the role of the transactivation domain (TAD) of KLF15 in angiotensin II (Ang II)-induced adventitial pathologic changes. KLF15 expression was decreased in the vascular adventitia of Ang II-infused mice (1000 ng/kg/min, 14 d) and in adventitial fibroblasts (AFs) stimulated by Ang II (10-7 M). Adenovirus-mediated KLF15 overexpression normalized Ang II-induced vascular hypertrophy, increased collagen deposition, macrophage infiltration, and CCL2 and VCAM-1 expression. Interestingly, KLF15-ΔTAD (KLF15 with deletion of TAD at amino acids 132-152) overexpression showed no effect on the above pathologic changes. Similarly, perivascularly overexpression of KLF15 but not KLF15-ΔTAD in carotid arteries also attenuated Ang II-induced vascular inflammation and fibrosis. Furthermore, KLF15 overexpression after Ang II infusion rescued Ang II-induced vascular remodeling. CCL2 or VCAM-1-mediated monocyte and macrophage migration or adhesion to AFs in response to Ang II was negatively regulated by KLF15 through TAD. Ang II-enhanced Smad2/3 activation and adventitial migration, proliferation, and differentiation of AFs were suppressed by KLF15 but not KLF15-ΔTAD overexpression. Conversely, small interfering RNA knockdown of KLF15 aggravated Ang II-induced Smad2/3 activation and dysfunction of AFs. Luciferase, coimmunoprecipitation, and chromatin immunoprecipitation assay were used to demonstrate that interaction of KLF15 with Smad2/3 suppressed CCL2 expression through TAD. Mechanistically, activation of Ang II type 1 receptor/phospholipase Cγ 1/ERK1/2 signaling resulted in a decrease of KLF15 expression. In conclusion, these results demonstrate that KLF15 negatively regulates activation of AFs through TAD, which plays an important role in Ang II-induced adventitial inflammation and fibrosis.-Lu, Y.-Y., Li, X.-D., Zhou, H.-D., Shao, S., He, S., Hong, M.-N., Liu, J.-C., Xu, Y.-L., Wu, Y.-J., Zhu, D.-L., Wang, J.-G., Gao, P.-J. Transactivation domain of Krüppel-like factor 15 negatively regulates angiotensin II-induced adventitial inflammation and fibrosis.

Association of ATP2B1 common variants with asymptomatic intracranial and extracranial large artery stenosis in hypertension patients.

BACKGROUND AND AIMS: Genetic factors play an important role in the cervico-cerebral large-artery atherosclerotic stenosis (LAS), and ATP2B1 gene has been associated with the process of atherosclerosis disorders, such as coronary artery disease and arterial stiffness. But there is little information about the relationship between ATP2B1 gene and atherosclerosis in the intracranial arteries. We hereby investigated the association of common variants in ATP2B1 gene with LAS in asymptomatic Chinese hypertension patients. METHODS: The stenosis of intracranial and extracranial arteries were evaluated in 899 subjects through computerized tomography angiography from the aortic arch to the skull base. A total of 11 ATP2B1 common variants were genotyped. Multivariate logistic regression was carried out in a dominant model with confounding factors adjusted. RESULTS: rs17249754-A (OR = 0.43, p = 0.0002) and rs1401982-G (OR = 0.47, p = 0.0007) were associated with decreased susceptibility of concurrent extra and intracranial stenosis even after Bonferroni correction. These two minor alleles were also significantly associated with less stenotic arteries and moderate-to-severe stenosis. CONCLUSION: rs17249754 and rs1401982 were associated with asymptomatic LAS in stroke-free Chinese hypertension patients and might benefit early recognition of LAS patients in clinical practice.

Developmental and functional characteristics of the thoracic aorta perivascular adipocyte.

Thoracic aorta perivascular adipose tissue (T-PVAT) has critical roles in regulating vascular homeostasis. However, the developmental characteristics and cellular lineage of adipocyte in the T-PVAT remain unclear. We show that T-PVAT contains three long strip-shaped fat depots, anterior T-PVAT (A-T-PVAT), left lateral T-PVAT (LL-T-PVAT), and right lateral T-PVAT (RL-T-PVAT). A-T-PVAT displays a distinct transcriptional profile and developmental origin compared to the two lateral T-PVATs (L-T-PVAT). Lineage tracing studies indicate that A-T-PVAT adipocytes are primarily derived from SM22α+ progenitors, whereas L-T-PVAT contains both SM22α+ and Myf5+ cells. We also show that L-T-PVAT contains more UCP1+ brown adipocytes than A-T-PVAT, and L-T-PVAT exerts a greater relaxing effect on aorta than A-T-PVAT. Angiotensin II-infused hypertensive mice display greater macrophage infiltration into A-T-PVAT than L-T-PVAT. These combined results indicate that L-T-PVAT has a distinct development from A-T-PVAT with different cellular lineage, and suggest that L-T-PVAT and A-T-PVAT have different physiological and pathological functions.

Suppression of Endothelial-to-Mesenchymal Transition by SIRT (Sirtuin) 3 Alleviated the Development of Hypertensive Renal Injury.

Endothelial-to-mesenchymal transition (EndoMT) has recently emerged as a potentially important contributor in promoting fibrosis in chronic kidney disease. However, little is known about the role and molecular basis of its involvement in hypertensive renal injury. Here, we aim to determine the role of SIRT (sirtuin) 3 on EndoMT in hypertensive renal injury and to explore its underlying mechanisms. We found that SIRT3 expression was significantly reduced in Ang II (angiotensin II)-induced hypertensive model, accompanied with induction of EndoMT and increased reactive oxygen species and renal fibrosis. In SIRT3-/- (SIRT3 knockout) mice subjected to Ang II infusion, renal dysfunction was aggravated with an increased EndoMT and reactive oxygen species level, whereas in SIRT3-TgEC (SIRT3 endothelial cell-specific transgenic) mice, the Ang II-induced renal fibrosis and EndoMT and oxidative stress were ameliorated. With primary mouse glomerular endothelial cells, we confirmed that Ang II treatment initiated EndoMT and decreased catalase expression, which were suppressed by SIRT3 overexpression. Using immunoprecipitation, luciferase, and chromatin immunoprecipitation assay, we demonstrated that SIRT3-mediated deacetylation and nuclear localization of Foxo3a (forkhead box O3a) resulted in activated Foxo3a-dependent catalase expression. Moreover, Foxo3a knockdown abolished SIRT3-mediated suppression of EndoMT. In conclusion, these results established the SIRT3-Foxo3a-catalase pathway as a critical factor in the maintenance of endothelial homeostasis and point to an important role of EndoMT in the vascular pathology of renal fibrosis, which may provide a new therapeutic target to impede the progression of hypertensive renal injury.

Perivascular Adipose Tissue-Derived PDGF-D Contributes to Aortic Aneurysm Formation During Obesity.

Obesity increases the risk of vascular diseases, including aortic aneurysm (AA). Perivascular adipose tissue (PVAT) surrounding arteries are altered during obesity. However, the underlying mechanism of adipose tissue, especially PVAT, in the pathogenesis of AA is still unclear. Here we showed that angiotensin II (AngII) infusion increases the incidence of AA in leptin-deficient obese mice (ob/ob) and high-fat diet-induced obese mice with adventitial inflammation. Furthermore, transcriptome analysis revealed that platelet-derived growth factor-D (PDGF-D) was highly expressed in the PVAT of ob/ob mice. Therefore, we hypothesized that PDGF-D mediates adventitial inflammation, which provides a direct link between PVAT dysfunction and AA formation in AngII-infused obese mice. We found that PDGF-D promotes the proliferation, migration, and inflammatory factors expression in cultured adventitial fibroblasts. In addition, the inhibition of PDGF-D function significantly reduced the incidence of AA in AngII-infused obese mice. More importantly, adipocyte-specific PDGF-D transgenic mice are more susceptible to AA formation after AngII infusion accompanied by exaggerated adventitial inflammatory and fibrotic responses. Collectively, our findings reveal a notable role of PDGF-D in the AA formation during obesity, and modulation of this cytokine might be an exploitable treatment strategy for the condition.

Deficiency of Complement C3a and C5a Receptors Prevents Angiotensin II-Induced Hypertension via Regulatory T Cells.

RATIONALE: Inflammation and immunity play crucial roles in the development of hypertension. Complement activation-mediated innate immune response is involved in the regulation of hypertension and target-organ damage. However, whether complement-mediated T-cell functions could regulate blood pressure elevation in hypertension is still unclear. OBJECTIVE: We aim to determine whether C3aR (complement component 3a receptor) and C5aR (complement component 5a receptor) could regulate blood pressure via modulating regulatory T cells (Tregs). METHODS AND RESULTS: We showed that angiotensin II (Ang II)-induced hypertension resulted in an elevated expression of C3aR and C5aR in Foxp3 (forkhead box P3)+ Tregs. By using C3aR and C5aR DKO (double knockout) mice, we showed that C3aR and C5aR deficiency together strikingly decreased both systolic and diastolic blood pressure in response to Ang II compared with WT (wild type), single C3aR-deficient (C3aR-/-), or C5aR-deficient (C5aR-/-) mice. Flow cytometric analysis showed that Ang II-induced Treg reduction in the kidney and blood was also blocked in DKO mice. Histological analysis indicated that renal and vascular structure remodeling and damage after Ang II treatment were attenuated in DKO mice compared with WT mice. In vitro, Ang II was able to stimulate C3aR and C5aR expression in cultured CD4+CD25+ natural Tregs. CD3 and CD28 antibody stimuli downregulated Foxp3 expression in WT but not DKO Tregs. More important, depletion of Tregs with CD25 antibody abolished the protective effects against Ang II-induced hypertension and target-organ damage in DKO mice. Adoptive transfer of DKO Tregs showed much more profound protective effects against Ang II-induced hypertension than WT Treg transfer. Furthermore, we demonstrated that C5aR expression in Foxp3+ Tregs was higher in hypertensive patients compared with normotensive individuals. CONCLUSIONS: C3aR and C5aR DKO-mediated Treg function prevents Ang II-induced hypertension and target-organ damage. Targeting C3aR and C5aR in Tregs specifically may be an alternative novel approach for hypertension treatment.

Osteoglycin attenuates cardiac fibrosis by suppressing cardiac myofibroblast proliferation and migration through antagonizing lysophosphatidic acid 3/matrix metalloproteinase 2/epidermal growth factor receptor signalling.

Aims: Cardiac myofibroblasts (CMFs) play a crucial role in the progression of pathological fibrotic cardiac remodelling. The expression of osteoglycin (OGN) is increased in diseased hearts; however, the role of OGN in pathological cardiac remodelling is not understood. Here, we sought to determine the effect of OGN on cardiac interstitial fibrosis and investigate the molecular mechanisms of OGN in CMF activation and matrix production. Methods and results: We found that OGN expression was significantly upregulated in mouse hearts in response to chronic 14-day angiotensin II (Ang II) infusion. Mice lacking OGN (OGN-/-) exhibited enhanced cardiac interstitial fibrosis and significantly more severe cardiac dysfunction following Ang II infusion compared to wild-type mice. OGN deficiency did not alter blood pressure, nor had effect on transforming growth factor-beta signalling activation, but presented with increased proliferative activity in hearts. In vitro studies with isolated CMFs revealed that OGN deficiency significantly increased proliferation and migration and enhanced the transactivation of epidermal growth factor receptor (EGFR) signalling by Ang II. On the other hand, OGN overexpression in CMFs decreased their proliferation and migration via reducing EGFR activation. Overexpression of OGN also suppressed the shedding of membrane anchored EGFR ligand. Moreover, OGN was found to interact with a lysophosphatidic acid (LPA) receptor isoform 3 and thus to attenuate EGFR transactivation through blocking cell surface translocation of membrane type 1 matrix metalloproteinase (MT1-MMP) and subsequent pro-MMP-2 activation in a Ras homolog gene family, member A (RhoA)/Rho-associated, coiled-coil containing protein kinase (ROCK)-dependent manner. Conclusion: These findings suggest that OGN negatively regulates cardiac fibrotic remodelling by attenuating CMF proliferation and migration through LPA3-mediated and Rho/ROCK-dependent inhibition of MT1-MMP translocation, MMP2 activation and EGFR transactivation.

Association of Homocysteine with Aysmptomatic Intracranial and Extracranial Arterial Stenosis in Hypertension Patients.

Elevated plasma homocysteine (Hcy) is suggested as an independent risk factor for stroke. We aimed to investigate the association of Hcy concentration with intracranial atherosclerosis (ICAS) and extracranial AS (ECAS) in hypertensive patients without stroke in Chinese population and to explore modified effect of methylenetetrahydrofolate reductase (MTHFR) C677T on their relationship. The stenosis of intracranial and extracranial arteries were evaluated in a total of 929 subjects through computerized tomographic angiography (CTA) from aortic arch to the skull base. Hcy concentration showed significantly association with both ICAS (OR: 1.105; 95% CI: 1.057-1.155) and ECAS (OR: 1.096; 95% CI: 1.047-1.146) for 1 µmol/L increment in Hcy. Meanwhile, hyperhomocysteinemia (≥15 µmol/L) was also displayed association with ICAS (OR: 1.587; 95% CI: 1.029-2.446) and ECAS (OR: 2.164; 95% CI: 1.392-3.364) after fully adjustment. Furthermore, in the subgroup analysis, such association remained significant only in the subjects that were younger, with normal renal function and with MTHFR 677 C allele. Our study showed the significant association of Hcy with ECAS and ICAS in asymptomatic hypertension patients. Hcy played a universal effect on the cervico-cerebral atherosclerosis. Such association was modified by the MTHFR C677T genotype.

Management of morning hypertension: a consensus statement of an Asian expert panel.

Morning blood pressure (BP) surge is an important aspect of hypertension research. Morning BP monitoring could be a clinically relevant concept in the therapeutic management of hypertension and in the prevention of cardiovascular complications by defining and treating morning hypertension. Because antihypertensive medication is often taken in the morning, uncontrolled morning BP during the trough effect hours could be a hallmark of inadequate choice of antihypertensive regimen, such as the use of short- or intermediate-acting drugs, underdosing of drugs, or no use or underuse of combination therapy. To improve the management of hypertension in general and morning hypertension in particular, long-acting antihypertensive drugs should be used in appropriate, often full dosages and in proper combinations. The clinical usefulness of antihypertensive drugs with specific mechanisms for morning BP or split or timed dosing of long-acting drugs in controlling morning BP remains under investigation.

Morning hypertension is more common in elderly hypertensive patients with controlled documented office blood pressure in primary care clinics: the Minhang study.

BACKGROUND: Increased morning blood pressure (BP) has been associated with fatal and nonfatal cardiovascular events, especially in Asians. METHOD: To detect the control status of home BP, we performed a home BP monitoring study, including elderly patients with hypertension who had controlled documented office BP in Chinese primary care clinics. In 707 participants from Xinzhuang County Hospital in Shanghai, the home BP was measured by a memory-equipped device three times daily for seven consecutive days. RESULTS: The prevalence of uncontrolled hypertension was 51.3% in the morning and 42% in the evening. Uncontrolled morning hypertension was associated with age [odds ratio (OR): 1.074; 95% confidence interval (CI): 1.041-1.108], office SBP (OR: 1.027; 95% CI: 1.015-1.039), office DBP (OR: 1.042; 95% CI: 1.021-1.064), and the number of antihypertensive drugs taken (OR: 1.387; 95% CI: 1.059-1.817), whereas it was inversely associated with the use of long-acting antihypertensive drugs (OR: 0.588; 95% CI: 0.355-0.973). Compared with office BP, the home morning BP showed a more significant association with age and short-acting antihypertensive drugs. CONCLUSION: The prevalence of uncontrolled home BP is high in elderly Chinese hypertensive patients, especially in the morning, and home BP monitoring might be a feasible method for detecting it. The use of long-acting antihypertensive drugs might help to improve morning hypertension.