Sex-specific relationships of inflammatory biomarkers with blood pressure in older adults.

Emerging evidence indicates an association between blood pressure and inflammation, yet this relationship remains unclear in older adults, despite the elevated prevalence of hypertension. We investigated the association between blood pressure, high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and white blood cell (WBC) count in a cohort of 3571 older adults aged 65 and above, and 587 middle-aged participants (55-59 years old). In women aged 65 and above, the relationship between inflammatory markers and blood pressure was consistent, with hs-CRP and WBC emerging as predictors of high blood pressure. For hs-CRP, the adjusted odds ratio (OR) was 1.5 (95% CI, 1.07 to 2.10, P = 0.02), and for WBC, the adjusted OR was 1.41 (95% CI, 1.02 to 1.94, P = 0.04), comparing the highest to the lowest quartiles. In men, only the WBC count was significantly associated with an increased OR for high BP (adjusted OR 1.49, 95% CI, 1.09 to 2.02, P = 0.01) across quartiles. Across the entire study population, in a fully adjusted model, all inflammatory markers were modestly associated with blood pressure levels, while the effect of being over 65 years was the most significant predictor of high blood pressure (OR 1.84, 95% CI, 1.50 to 2.25, P < 0.001). The link between key inflammation markers and blood pressure in older adults varies by sex and biomarker type and may differ from the relationship observed in younger individuals. These relationships are likely to be affected by factors linked to age.

Interplay Between Plasma Glycine and Branched-Chain Amino Acids Contributes to the Development of Hypertension and Coronary Heart Disease.

BACKGROUND: Higher levels of plasma glycine are linked to a reduced risk, while increased levels of total branched-chain amino acids (tBCAAs) are associated with a higher risk of essential hypertension and coronary heart disease (CHD). As these metabolic components are interconnected, analyzing the tBCAAs/glycine ratio may help to understand their interplay in the pathogenesis of cardiovascular disease. METHODS: The Cox regression approach was combined with the development of novel genetic tools for assessments of associations between plasma metabolomic data (glycine, tBCAAs, and tBCAAs/glycine ratio) from the UK Biobank and the development of hypertension and CHD. Genome-wide association study was performed on 186 523 White UK Biobank participants to identify new independent genetic instruments for the 2-sample Mendelian randomization analyses. P-gain statistic >10 identified instruments associated with tBCAAs/glycine ratio significantly stronger compared with individual amino acids. Outcomes of genome-wide association study on hypertension and CHD were derived from the UK Biobank (nonoverlapping sample), FinnGen, and CARDIoGRAMplusC4D. RESULTS: The tBCAAs/glycine ratio was prospectively associated with a higher risk of developing hypertension and CHD (hazard ratio quintile Q5 versus Q1, 1.196 [95% CI, 1.109-1.289] and 1.226 [95% CI, 1.160-1.296], respectively). Mendelian randomization analysis demonstrated that tBCAAs/glycine ratio (P-gain >10) was a risk factor for hypertension (meta-analyzed inverse-variance weighted causal estimate 0.45 log odds ratio/SD (95% CI, 0.26-0.64) and CHD (0.48 [95% CI, 0.29-0.67]) with an absolute effect significantly larger compared with the effect of glycine (-0.06 [95% CI, -0.1 to -0.03] and -0.08 [95% CI, -0.11 to -0.05], respectively) or tBCAAs (0.22 [95% CI, 0.09-0.34] and 0.12 [95% CI, 0.01-0.24], respectively). CONCLUSIONS: The total BCAAs/glycine ratio is a key element of the metabolic signature contributing to hypertension and CHD, which may reflect biological pathways shared by glycine and tBCAAs.

Immunology in COPD and the use of combustible cigarettes and heated tobacco products.

Chronic obstructive pulmonary disease (COPD) is one of the most common chronic respiratory diseases, characterised by high morbidity and mortality. COPD is characterised by a progressive decline of lung function caused by chronic inflammatory reactions in the lung tissue due to continual exposure to harmful molecules by inhalation. As prevention plays a very important role in COPD, quitting smoking is the most important factor in reducing the decline in lung function. Unfortunately, many people are unable to break their nicotine addiction. This paper summarises current knowledge about combustible cigarettes (CSs) and alternative tobacco products such as heated tobacco products (HTPs) in COPD. The paper focuses on the immunological aspects of COPD and the influence of tobacco products on lung tissue immunology. There are differences in research results between HTPs and CSs in favour of HTPs. More long-term studies are needed to look at the effects of HTPs, especially in COPD. However, there is no doubt that it would be best for patients to give up their nicotine addiction completely.

Systemic and local vascular inflammation and arterial reactive oxygen species generation in patients with advanced cardiovascular diseases.

Background: Systemic inflammation may cause endothelial activation, mediate local inflammation, and accelerate progression of atherosclerosis. We examined whether the levels of circulating inflammatory cytokines reflect local vascular inflammation and oxidative stress in two types of human arteries. Methods: Human internal mammary artery (IMA) was obtained in 69 patients undergoing coronary artery bypass graft (CABG) surgery and left anterior descending (LAD) artery was obtained in 17 patients undergoing heart transplantation (HTx). Plasma levels of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) were measured using ELISA, high-sensitivity C-reactive protein (hs-CRP) was measured using Luminex, and mRNA expression of proinflammatory cytokines in the vascular tissues was assessed. Furthermore, formation of superoxide anion was measured in segments of IMA using 5 uM lucigenin-dependent chemiluminescence. Vascular reactivity was measured using tissue organ bath system. Results: TNF-α, IL-6 and IL-1ß mRNAs were expressed in all studied IMA and LAD segments. Plasma levels of inflammatory cytokines did not correlate with vascular cytokine mRNA expression neither in IMA nor in LAD. Plasma TNF-α and IL-6 correlated with hs-CRP level in CABG group. Hs-CRP also correlated with TNF-α in HTx group. Neither vascular TNF-α, IL-6 and IL-1ß mRNA expression, nor systemic levels of either TNF-α, IL-6 and IL-1ß were correlated with superoxide generation in IMAs. Interestingly, circulating IL-1ß negatively correlated with maximal relaxation of the internal mammary artery (r = -0.37, p = 0.004). At the same time the mRNA expression of studied inflammatory cytokines were positively associated with each other in both IMA and LAD. The positive correlations were observed between circulating levels of IL-6 and TNF-α in CABG cohort and IL-6 and IL-1ß in HTx cohort. Conclusions: This study shows that peripheral inflammatory cytokine measurements may not reflect local vascular inflammation or oxidative stress in patients with advanced cardiovascular disease (CVD). Circulating pro-inflammatory cytokines generally correlated positively with each other, similarly their mRNA correlated in the arterial wall, however, these levels were not correlated between the studied compartments.

Genetic analyses identify brain structures related to cognitive impairment associated with elevated blood pressure.

BACKGROUND AND AIMS: Observational studies have linked elevated blood pressure (BP) to impaired cognitive function. However, the functional and structural changes in the brain that mediate the relationship between BP elevation and cognitive impairment remain unknown. Using observational and genetic data from large consortia, this study aimed to identify brain structures potentially associated with BP values and cognitive function. METHODS AND RESULTS: Data on BP were integrated with 3935 brain magnetic resonance imaging-derived phenotypes (IDPs) and cognitive function defined by fluid intelligence score. Observational analyses were performed in the UK Biobank and a prospective validation cohort. Mendelian randomisation (MR) analyses used genetic data derived from the UK Biobank, International Consortium for Blood Pressure, and COGENT consortium. Mendelian randomisation analysis identified a potentially adverse causal effect of higher systolic BP on cognitive function [-0.044 standard deviation (SD); 95% confidence interval (CI) -0.066, -0.021] with the MR estimate strengthening (-0.087 SD; 95% CI -0.132, -0.042), when further adjusted for diastolic BP. Mendelian randomisation analysis found 242, 168, and 68 IDPs showing significant (false discovery rate P < 0.05) association with systolic BP, diastolic BP, and pulse pressure, respectively. Most of these IDPs were inversely associated with cognitive function in observational analysis in the UK Biobank and showed concordant effects in the validation cohort. Mendelian randomisation analysis identified relationships between cognitive function and the nine of the systolic BP-associated IDPs, including the anterior thalamic radiation, anterior corona radiata, or external capsule. CONCLUSION: Complementary MR and observational analyses identify brain structures associated with BP, which may be responsible for the adverse effects of hypertension on cognitive performance.

Novel biomarkers and emerging tools to identify causal molecular pathways in hypertension and associated cardiovascular diseases.

Hypertension (HT) is a modifiable risk factor for life-threatening cardiovascular diseases (CVDs) including coronary artery disease, heart failure, or stroke. Despite significant progress in understanding the pathophysiological mechanisms of the disease, the molecular pathways targeted by HT treatment remain largely unchanged. This warrants the need for finding novel biomarkers, which are causally related to persistent high blood pressure (BP) and may be pharmacologically targeted. Analytical output derived from large-scale biobanks, containing high-throughput genetic and biochemical data, such as OLINK and SomaScan-based proteomics or Nuclear Magnetic Resonance-based metabolomics, as well as novel analytical tools including the Mendelian randomization (MR) approach, enabling genetic causal inference, may create new treatment opportunities for HT and related CVDs. MR analysis may constitute additional evidence for observational studies and facilitate selection of drug targets for clinical testing and has been already used to nominate potentially causal biomarkers for HT and CVDs such as circulating glycine, branched-chain amino acids, lipoprotein(a), insulin-like growth factor 1, or fibronectin 1. Using the MR framework, genetic proxies for targets of already known drugs, such as statins, PCSK9, and ACE inhibitors, may additionally be informative about potential side effects and eventually contribute to more personalized medicine. Finally, genetic causal inference may disentangle independent direct effects of correlated traits such as lipid classes or markers of inflammation on cardiovascular clinical outcomes such as atherosclerosis and HT. While several novel HT-targeting drugs are currently under clinical investigation (e.g. brain renin-angiotensin-aldosterone system inhibitors or endothelin-1 receptor antagonists), analysis of high-throughput proteomic and metabolomic data from well-powered studies may deliver novel druggable molecular targets for HT and associated CVDs.

Serum and Vascular Stiffness Biomarkers Associated with the Severity of Degenerative Aortic Valve Stenosis and Cardiovascular Outcomes.

Background: Although degenerative aortic valve stenosis (DAS) is the most prevalent growth-up congestive heart valve disease, still little known about relationships between DAS severity, vascular stiffness (VS), echocardiographic parameters, and serum biomarkers in patients undergoing transcatheter (TAVR) or surgical aortic valve replacement (SAVR). The objective of this study was to identify biomarkers associated with DAS severity, and those that are associated with cardiovascular death (CVD) and episodes of chronic heart failure (CHF) exacerbation. Methods: A total of 137 patients with initially moderate-to-severe DAS were prospectively evaluated for the relationship between DAS severity, baseline VS, and serum biomarkers (uPAR, GDF-15, Gal-3, IL-6Rα, ET-1, PCSK9, RANTES/CCL5, NT-proBNP, and hs-TnT), and were followed-up for 48 months. The prognostic significance of each variable for CVD and CHF risk was measured by hazard ratio of risk (HR), which was calculated by Cox's proportional hazard model. Results: DAS severity showed correlations with IL-6Rα (r = 0.306, p < 0.001), uPAR (r = 0.184, p = 0.032), and NT-proBNP (r = −0.389, p < 0.001). Levels of ET-1 and Gal-3 were strongly correlated with VS parameters (r = 0.674, p < 0.001; r = 0.724, p < 0.001). Out of 137 patients, 20 were referred to TAVR, 88 to SAVR, and 29 to OMT. In TAVR patients, the highest levels of ET-1, Gal-3, and VS were found as compared to other patients. The highest incidence of CVD was observed in patients who underwent TAVR (35%), compared to SAVR (8%) and OMT (10.3%) (p = 0.004). In a multivariate analysis, ET-1 occurred predictive of CVD risk (HR 25.1, p = 0.047), while Gal-3 > 11.5 ng/mL increased the risk of CHF exacerbation episodes requiring hospital admission by 12%. Conclusions: Our study indicated that ET-1 and Gal-3 levels may be associated with the outcomes in patients with DAS.

Breast cancer chemotherapy induces vascular dysfunction and hypertension through a NOX4-dependent mechanism.

Cardiovascular disease is the major cause of morbidity and mortality in breast cancer survivors. Chemotherapy contributes to this risk. We aimed to define the mechanisms of long-term vascular dysfunction caused by neoadjuvant chemotherapy (NACT) and identify novel therapeutic targets. We studied arteries from postmenopausal women who had undergone breast cancer treatment using docetaxel, doxorubicin, and cyclophosphamide (NACT) and from women with no history of such treatment matched for key clinical parameters. We explored mechanisms in WT and Nox4-/- mice and in human microvascular endothelial cells. Endothelium-dependent, NO-mediated vasodilatation was severely impaired in patients after NACT, while endothelium-independent responses remained normal. This was mimicked by a 24-hour exposure of arteries to NACT agents ex vivo. When applied individually, only docetaxel impaired endothelial function in human vessels. Mechanistic studies showed that NACT increased inhibitory eNOS phosphorylation of threonine 495 in a Rho-associated protein kinase-dependent (ROCK-dependent) manner and augmented vascular superoxide and hydrogen peroxide production and NADPH oxidase activity. Docetaxel increased expression of the NADPH oxidase NOX4 in endothelial and smooth muscle cells and NOX2 in the endothelium. A NOX4 increase in human arteries may be mediated epigenetically by diminished DNA methylation of the NOX4 promoter. Docetaxel induced endothelial dysfunction and hypertension in mice, and these were prevented in Nox4-/- mice and by pharmacological inhibition of Nox4 or Rock. Commonly used chemotherapeutic agents and, in particular, docetaxel alter vascular function by promoting the inhibitory phosphorylation of eNOS and enhancing ROS production by NADPH oxidases.

Th17/Treg imbalance in patients with primary hyperaldosteronism and resistant hypertension.

INTRODUCTION: Inflammation plays a pivotal role in blood pressure regulation. Data on experimental models of hypertension and hypertensive patients reflect the imbalance between T regulatory (Treg) and Th17 effector cells (Th17). OBJECTIVES: The aim of this study was to quantify peripheral blood Treg lymphocytes and Th17 subsets in individuals with primary hyperaldosteronism (PHA) and resistant hypertension (RHT) presenting with elevated blood pressure levels and augmented cardiovascular risk when compared with normotensive controls (CTRL). PATIENTS AND METHODS: Twenty CTRL participants, 21 patients with PHA, and 20 patients with RHT were enrolled. Plasma renin and angiotensin II, serum aldosterone concentration, ambulatory blood pressure monitoring (ABPM), echocardiography, clinical data, and phenotype of peripheral blood cells were assessed. RESULTS: There were no statistically significant differences in terms of age and sex between the groups. Similar systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels in ABPM were observed in individuals with PHA and RHT. PHA patients had lower angiotensin II and 4­fold higher aldosterone concentrations than CTRL patients. Both, PHA and RHT were associated with cardiac hypertrophy and coronary artery disease. RHT patients presented a significantly higher CD4+IL­17A+ T cell number when compared with PHA and CTRL ones. The number of CD4+CD25+FOXP3+ T cells did not differ between patients with secondary hypertension and normotensive controls. Finally, positive correlations between the data on 24 h SBP and the content of CD4+IL­17A+ and CD4+CD25+FOXP3+ in the PHA were found. CONCLUSIONS: Elevated 24 h SBP in PHA was associated with the increased numbers of CD4+IL­17 and CD4+CD25+FOXP3+ T cells.

Silencing of Sphingosine kinase 1 Affects Maturation Pathways in Mouse Neonatal Cardiomyocytes.

Sphingosine kinase-1 (Sphk1) and its product, sphingosine-1-phosphate (S1P) are important regulators of cardiac growth and function. Numerous studies have reported that Sphk1/S1P signaling is essential for embryonic cardiac development and promotes pathological cardiac hypertrophy in adulthood. However, no studies have addressed the role of Sphk1 in postnatal cardiomyocyte (CM) development so far. The present study aimed to assess the molecular mechanism(s) by which Sphk1 silencing might influence CMs development and hypertrophy in vitro. Neonatal mouse CMs were transfected with siRNA against Sphk1 or negative control, and subsequently treated with 1 µM angiotensin II (AngII) or a control buffer for 24 h. The results of RNASeq analysis revealed that diminished expression of Sphk1 significantly accelerated neonatal CM maturation by inhibiting cell proliferation and inducing developmental pathways in the stress (AngII-induced) conditions. Importantly, similar effects were observed in the control conditions. Enhanced maturation of Sphk1-lacking CMs was further confirmed by the upregulation of the physiological hypertrophy-related signaling pathway involving Akt and downstream glycogen synthase kinase 3 beta (Gsk3ß) downregulation. In summary, we demonstrated that the Sphk1 silencing in neonatal mouse CMs facilitated their postnatal maturation in both physiological and stress conditions.

Hypertensive Effect of Downregulation of the Opioid System in Mouse Model of Different Activity of the Endogenous Opioid System.

The opioid system is well-known for its role in modulating nociception and addiction development. However, there are premises that the endogenous opioid system may also affect blood pressure. The main goal of the present study was to determine the impact of different endogenous opioid system activity and its pharmacological blockade on blood pressure. Moreover, we examined the vascular function in hyper- and hypoactive states of the opioid system and its pharmacological modification. In our study, we used two mouse lines which are divergently bred for high (HA) and low (LA) swim stress-induced analgesia. The obtained results indicated that individuals with low endogenous opioid system activity have higher basal blood pressure compared to those with a hyperactive opioid system. Additionally, naloxone administration only resulted in the elevation of blood pressure in HA mice. We also showed that the hypoactive opioid system contributes to impaired vascular relaxation independent of endothelium, which corresponded with decreased guanylyl cyclase levels in the aorta. Together, these data suggest that higher basal blood pressure in LA mice is a result of disturbed mechanisms in vascular relaxation in smooth muscle cells. We believe that a novel mechanism which involves endogenous opioid system activity in the regulation of blood pressure will be a promising target for further studies in hypertension development.

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p22phox subunit polymorphisms, systemic oxidative stress, endothelial dysfunction, and atherosclerosis in type 2 diabetes mellitus.

INTRODUCTION: Diabetes mellitus is an important and rapidly increasing problem in public health. It associates with endothelial dysfunction and increased endothelial permeability, which may lead to severe cardiovascular events. OBJECTIVES: We aimed to evaluate the relationship between polymorphisms in the cytochrome b-245 alpha chain (CYBA) gene encoding p22phox, a key subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, with endothelial function, atherosclerosis and systemic oxidative stress in type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: Intima-media thickness (IMT), flow- and nitroglycerin-mediated dilatation (FMD and NMD) were measured in 182 patients with T2DM. Assessment of plasma levels of von Willebrand factor (vWF) and malondialdehyde (MDA) levels as well as genotyping of coding sequence C242T (rs4673) and promoter region A-930G (rs9932581) polymorphisms of CYBA were performed using standardized protocols. RESULTS: We observed a significant association of the impaired endothelial function, as measured by FMD, with the C allele of C242T, but not with the A-930G polymorphism. Functional relationship of the C242T polymorphism with endothelial dysfunction remained significant following a multivariable adjustment for major risk factors for atherosclerosis. Mean IMT, NMD, concentrations of MDA or vWF were not related to the specific genotypes of the investigated polymorphisms. CONCLUSIONS: C242T, but not A-930G, polymorphism of CYBA significantly affects endothelial function in T2DM. Thus, it might be a useful marker of endothelial dysfunction in T2DM patients.

Periodontal therapy and treatment of hypertension-alternative to the pharmacological approach. A systematic review and meta-analysis.

AIM: Quantitative comparison of the effects of intensive (IPT) or conventional (CPT) periodontal treatment on arterial blood pressure, endothelial function and inflammatory/metabolic biomarkers. MATERIALS AND METHODS: A systematic search was conducted to identify randomized controlled trials (RCT) of IPT (supra and subgingival instrumentation). Eight RCTs were included in the meta-analysis. Difference in change of systolic blood pressure (SBP) and diastolic blood pressure (DBP) before and after IPT or CPT were the primary outcomes. The secondary outcomes included: endothelial function and selected inflammatory/anti-inflammatory (CRP, IL-6, IL-10, IFN-γ) and metabolic biomarkers (HDL, LDL, TGs). RESULTS: The overall effect estimates (pooled Weighted Mean Difference (WMD)) of the primary outcome for SBP and DBP was -4.3 mmHg [95%CI: -9.10-0.48], p = 0.08 and -3.16 mmHg [95%CI: -6.51-0.19], p = 0.06 respectively. These studies were characterized by high heterogeneity. Therefore, random effects model for meta-analysis was performed. Sub-group analyses confirmed statistically significant reduction in SBP [WMD = -11.41 mmHg (95%CI: -13.66, -9.15) P < 0.00001] and DBP [WMD = -8.43 mmHg (95%CI: -10.96,-5.91)P < 0.00001] after IPT vs CPT among prehypertensive/hypertensive patients, while this was not observed in normotensive individuals. The meta-analyses showed significant reductions in CRP and improvement of endothelial function following IPT at all analysed timepoints. CONCLUSIONS: IPT leads to improvement of the cardiovascular health in hypertensive and prehypertensive individuals.

White Blood Cells and Blood Pressure: A Mendelian Randomization Study.

BACKGROUND: High blood pressure (BP) is a risk factor for cardiovascular morbidity and mortality. While BP is regulated by the function of kidney, vasculature, and sympathetic nervous system, recent experimental data suggest that immune cells may play a role in hypertension. METHODS: We studied the relationship between major white blood cell types and blood pressure in the UK Biobank population and used Mendelian randomization (MR) analyses using the ≈750 000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies to examine which leukocyte populations may be causally linked to BP. RESULTS: A positive association between quintiles of lymphocyte, monocyte, and neutrophil counts, and increased systolic BP, diastolic BP, and pulse pressure was observed (eg, adjusted systolic BP mean±SE for 1st versus 5th quintile respectively: 140.13±0.08 versus 141.62±0.07 mm Hg for lymphocyte, 139.51±0.08 versus 141.84±0.07 mm Hg for monocyte, and 137.96±0.08 versus 142.71±0.07 mm Hg for neutrophil counts; all P<10-50). Using 121 single nucleotide polymorphisms in MR, implemented through the inverse-variance weighted approach, we identified a potential causal relationship of lymphocyte count with systolic BP and diastolic BP (causal estimates: 0.69 [95% CI, 0.19-1.20] and 0.56 [95% CI, 0.23-0.90] of mm Hg per 1 SD genetically elevated lymphocyte count, respectively), which was directionally concordant to the observational findings. These inverse-variance weighted estimates were consistent with other robust MR methods. The exclusion of rs3184504 SNP in the SH2B3 locus attenuated the magnitude of the signal in some of the MR analyses. MR in the reverse direction found evidence of positive effects of BP indices on counts of monocytes, neutrophils, and eosinophils but not lymphocytes or basophils. Subsequent MR testing of lymphocyte count in the context of genetic correlation with renal function or resting and postexercise heart rate demonstrated a positive association of lymphocyte count with urine albumin-to-creatinine ratio. CONCLUSIONS: Observational and genetic analyses demonstrate a concordant, positive and potentially causal relationship of lymphocyte count with systolic BP and diastolic BP.

T-Cell-Derived miRNA-214 Mediates Perivascular Fibrosis in Hypertension.

RATIONALE: Despite increasing understanding of the prognostic importance of vascular stiffening linked to perivascular fibrosis in hypertension, the molecular and cellular regulation of this process is poorly understood. OBJECTIVES: To study the functional role of microRNA-214 (miR-214) in the induction of perivascular fibrosis and endothelial dysfunction driving vascular stiffening. METHODS AND RESULTS: Out of 381 miRs screened in the perivascular tissues in response to Ang II (angiotensin II)-mediated hypertension, miR-214 showed the highest induction (8-fold, P=0.0001). MiR-214 induction was pronounced in perivascular and circulating T cells, but not in perivascular adipose tissue adipocytes. Global deletion of miR-214-/- prevented Ang II-induced periaortic fibrosis, Col1a1, Col3a1, Col5a1, and Tgfb1 expression, hydroxyproline accumulation, and vascular stiffening, without difference in blood pressure. Mechanistic studies revealed that miR-214-/- mice were protected against endothelial dysfunction, oxidative stress, and increased Nox2, all of which were induced by Ang II in WT mice. Ang II-induced recruitment of T cells into perivascular adipose tissue was abolished in miR-214-/- mice. Adoptive transfer of miR-214-/- T cells into RAG1-/- mice resulted in reduced perivascular fibrosis compared with the effect of WT T cells. Ang II induced hypertension caused significant change in the expression of 1380 T cell genes in WT, but only 51 in miR-214-/-. T cell activation, proliferation and chemotaxis pathways were differentially affected. MiR-214-/- prevented Ang II-induction of profibrotic T cell cytokines (IL-17, TNF-α, IL-9, and IFN-γ) and chemokine receptors (CCR1, CCR2, CCR4, CCR5, CCR6, and CXCR3). This manifested in reduced in vitro and in vivo T cell chemotaxis resulting in attenuation of profibrotic perivascular inflammation. Translationally, we show that miR-214 is increased in plasma of patients with hypertension and is directly correlated to pulse wave velocity as a measure of vascular stiffness. CONCLUSIONS: T-cell-derived miR-214 controls pathological perivascular fibrosis in hypertension mediated by T cell recruitment and local profibrotic cytokine release.

Cardiovascular Effects of Pharmacological Targeting of Sphingosine Kinase 1.

High blood pressure is a risk factor for cardiovascular diseases. Ang II (angiotensin II), a key pro-hypertensive hormone, mediates target organ consequences such as endothelial dysfunction and cardiac hypertrophy. S1P (sphingosine-1-phosphate), produced by Sphk1 (sphingosine kinase 1), plays a pivotal role in the pathogenesis of hypertension and downstream organ damage, as it controls vascular tone and regulates cardiac remodeling. Accordingly, we aimed to examine if pharmacological inhibition of Sphk1 using selective inhibitor PF543 can represent a useful vasoprotective and cardioprotective anti-hypertensive strategy in vivo. PF543 was administered intraperitoneally throughout a 14-day Ang II-infusion in C57BL6/J male mice. Pharmacological inhibition of Sphk1 improved endothelial function of arteries of hypertensive mice that could be mediated via decrease in eNOS (endothelial nitric oxide synthase) phosphorylation at T495. This effect was independent of blood pressure. Importantly, PF543 also reduced cardiac hypertrophy (heart to body weight ratio, 5.6±0.2 versus 6.4±0.1 versus 5.9±0.2 mg/g; P<0.05 for Sham, Ang II+placebo, and Ang II+PF543-treated mice, respectively). Mass spectrometry revealed that PF543 elevated cardiac sphingosine, that is, Sphk1 substrate, content in vivo. Mechanistically, RNA-Seq indicated a decreased expression of cardiac genes involved in actin/integrin organization, S1pr1 signaling, and tissue remodeling. Indeed, downregulation of Rock1 (Rho-associated coiled-coil containing protein kinase 1), Stat3 (signal transducer and activator of transcription 3), PKC (protein kinase C), and ERK1/2 (extracellular signal-regulated kinases 1/2) level/phosphorylation by PF543 was observed. In summary, pharmacological inhibition of Sphk1 partially protects against Ang II-induced cardiac hypertrophy and endothelial dysfunction. Therefore, it may represent a promising target for harnessing residual cardiovascular risk in hypertension.

Causal association between periodontitis and hypertension: evidence from Mendelian randomization and a randomized controlled trial of non-surgical periodontal therapy.

AIMS: Inflammation is an important driver of hypertension. Periodontitis is a chronic inflammatory disease, which could provide a mechanism for pro-hypertensive immune activation, but evidence of a causal relationship in humans is scarce. We aimed to investigate the nature of the association between periodontitis and hypertension. METHODS AND RESULTS: We performed a two-sample Mendelian randomization analysis in the ∼750 000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies participants using single nucleotide polymorphisms (SNPs) in SIGLEC5, DEFA1A3, MTND1P5, and LOC107984137 loci GWAS-linked to periodontitis, to ascertain their effect on blood pressure (BP) estimates. This demonstrated a significant relationship between periodontitis-linked SNPs and BP phenotypes. We then performed a randomized intervention trial on the effects of treatment of periodontitis on BP. One hundred and one hypertensive patients with moderate/severe periodontitis were randomized to intensive periodontal treatment (IPT; sub- and supragingival scaling/chlorhexidine; n = 50) or control periodontal treatment (CPT; supragingival scaling; n = 51) with mean ambulatory 24-h (ABPM) systolic BP (SBP) as primary outcome. Intensive periodontal treatment improved periodontal status at 2 months, compared to CPT. This was accompanied by a substantial reduction in mean SBP in IPT compared to the CPT (mean difference of -11.1 mmHg; 95% CI 6.5-15.8; P < 0.001). Systolic BP reduction was correlated to periodontal status improvement. Diastolic BP and endothelial function (flow-mediated dilatation) were also improved by IPT. These cardiovascular changes were accompanied by reductions in circulating IFN-γ and IL-6 as well as activated (CD38+) and immunosenescent (CD57+CD28null) CD8+T cells, previously implicated in hypertension. CONCLUSION: A causal relationship between periodontitis and BP was observed providing proof of concept for development of clinical trial in a large cohort of hypertensive patients. ClinicalTrials.gov: NCT02131922.