Proteomic Analysis of Prehypertensive and Hypertensive Patients: Exploring the Role of the Actin Cytoskeleton.

Hypertension is a pervasive and widespread health condition that poses a significant risk factor for cardiovascular disease, which includes conditions such as heart attack, stroke, and heart failure. Despite its widespread occurrence, the exact cause of hypertension remains unknown, and the mechanisms underlying the progression from prehypertension to hypertension require further investigation. Recent proteomic studies have shown promising results in uncovering potential biomarkers related to disease development. In this study, serum proteomic data collected from Qatar Biobank were analyzed to identify altered protein expression between individuals with normal blood pressure, prehypertension, and hypertension and to elucidate the biological pathways contributing to this disease. The results revealed a cluster of proteins, including the SRC family, CAMK2B, CAMK2D, TEC, GSK3, VAV, and RAC, which were markedly upregulated in patients with hypertension compared to those with prehypertension (fold change ≥ 1.6 or ≤-1.6, area under the curve ≥ 0.8, and q-value < 0.05). Pathway analysis showed that the majority of these proteins play a role in actin cytoskeleton remodeling. Actin cytoskeleton reorganization affects various biological processes that contribute to the maintenance of blood pressure, including vascular tone, endothelial function, cellular signaling, inflammation, fibrosis, and mechanosensing. Therefore, the findings of this study suggest a potential novel role of actin cytoskeleton-related proteins in the progression from prehypertension to hypertension. The present study sheds light on the underlying pathological mechanisms involved in hypertension and could pave the way for new diagnostic and therapeutic approaches for the treatment of this disease.

Clinical impact of pre-hypertension on the risk of cancer in male and female subjects.

There are few studies assessing pre-hypertension and an impaired fasting glucose (IFG) and their combined effects on the cancer risk. We investigated the impact of pre-hypertension on cancer risk and IFG, and their combined effects on the cancer risk. This study included 371,762 subjects (≥40 years) who had never been diagnosed with hypertension, diabetes mellitus (DM), and cancer before. During a mean follow-up of 10.06 ± 1.86 years, 35,605 (9.58%) of the subjects developed cancer. In men only, cancer risk was significantly increased with an increase in the blood pressure (BP) (P for trend < 0.001), and were increased in the hypertension range, but not the pre-hypertension range. When analyzing the combination effect of BP and fasting glucose, cancer risks were serially increased with an increase in the fasting glucose in a dose-dependent manner, but not with an increase in BP. These results were more consistently significant in the never-smoker and non-alcohol drinking groups. However, in women, there was no significant difference. In conclusions, increased BP status or the fasting serum glucose level status were associated with cancer risk in men. Furthermore, the combination of both pre-hypertension and IFG also was associated with a cancer risk in men.

Defective Renal Angiotensin III and AT2 Receptor Signaling in Prehypertensive Spontaneously Hypertensive Rats.

Background Previous studies demonstrated that angiotensin (Ang) III , not Ang II , is the predominant endogenous agonist for Ang type-2 receptor ( AT 2R)-induced natriuresis in normal rats, and that hypertensive 12-week-old spontaneously hypertensive rats ( SHR ) lack natriuretic responses to Ang III . This study tested whether prehypertensive SHR already have defective Ang III -induced natriuresis and determined possible mechanisms. Methods and Results Female and male normotensive 4-week-old SHR and Wistar Kyoto rats were studied after 24-hour systemic AT 1R blockade. Left kidneys received 30 minute renal interstitial infusions of vehicle followed by Ang III (3.5, 7.0, 14, and 28 nmol/kg per min; each dose for 30 minutes). Right kidneys received vehicle infusions. In 4-week-old Wistar Kyoto rats, renal interstitial Ang III increased urine sodium (Na+) excretion but failed to induce natriuresis in 4-week-old SHR . Renal Ang III levels were similar between Wistar Kyoto rats and SHR , making increased Ang III degradation as a possible cause for defective natriuresis in SHR unlikely. In Wistar Kyoto rats, renal interstitial Ang III induced translocation of AT 2Rs to apical plasma membranes of renal proximal tubule cells. Simultaneously, Ang III induced retraction of the major Na+ transporter Na+-H+ exchanger-3 ( NHE -3) from apical membranes and internalization of Na+/K+ ATP ase ( NKA ) from basolateral membranes of renal proximal tubule cells. Consistent with NHE -3 and NKA retraction, Ang III increased pS er552- NHE -3 and decreased pS er23- NKA . In contrast, in SHR , intrarenal Ang III failed to induce AT 2R translocation, NHE -3 or NKA retraction, pS er552- NHE -3 phosphorylation, or pS er23- NKA dephosphorylation. Conclusions These results indicate impaired Ang III / AT 2R signaling as a possible primary defect in prehypertensive SHR .

Blockade of TLR4 Within the Paraventricular Nucleus Attenuates Blood Pressure by Regulating ROS and Inflammatory Cytokines in Prehypertensive Rats.

BACKGROUND: Toll-like receptor 4 (TLR4) has been implicated in the progression of cardiovascular disease, including hypertension. However, the role of TLR4 in the development of prehypertension is uncertain. METHODS: Prehypertensive rats were treated with 8% salt for 12 weeks to induce prehypertension. These rats were then given either TAK-242 selective TLR4 blocker, or vehicle by bilateral micro-injection to the paraventricular nucleus (PVN). Blood pressure (BP) and renal sympathetic nerve activity were recorded. PVN expression of TLR4, myeloid differentiation factor 88 (Myd88), nuclear factor-kappa B (NF-κB) p65, proinflammation cytokines (PICs), interleukin (IL)-1ß, IL-6, tumor necrosis factor-alpha (TNF-α), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), NADPH oxidase 4 (NOX4), Cu/Zn superoxide dismutase (SOD) level, tyrosine hydroxylase, and 67 kDa isoform of glutamate decarboxylase (GAD67) were tested to determine the influence of TLR4 blockade. RESULTS: TLR4 expression increased significantly in the PVN of high-salt groups with a corresponding increase in reactive oxygen species (ROS) and PICs. TLR4 blockade significantly reduced the signaling molecules downstream TLR4 and the expression of TNF-α, IL-6, IL-1ß, decreased ROS, NOX2, NOX4 level, increased Cu/Zn-SOD, re-balanced neurotransmitters, and regulated sympathetic nerve activity in the PVN of prehypertensive rats. CONCLUSIONS: Salt-induced prehypertension is partly due to the upregulation of TLR4 in PVN. Blockade of TLR4 in the brain reduced salt-induced prehypertension response, possibly through downregulation of ROS and PICs expression, and the restorage of neurotransmitter balance in the PVN.

Early short-term treatment with exogenous hydrogen sulfide postpones the transition from prehypertension to hypertension in spontaneously hypertensive rat.

ABSTACT Hydrogen sulfide (H2S), nitric oxide (NO), and renin-angiotensin system (RAS) are involved in hypertension. We examined whether early treatment with sodium hydrosulfide (NaHS), an exogenous H2S donor, can regulate H2S-generating pathway, NO pathway, and the RAS, to prevent the transition from prehypertension to hypertension in spontaneously hypertensive rats (SHRs). Four-week-old SHRs and control normotensive Wistar-Kyoto (WKY) rats were assigned into three groups: WKY, SHRs, and SHR + NaHS; SHRs were injected intraperitoneally with sodium hydrosulfide (14 µmol/kg/day) for 4 weeks. SHRs exhibited hypertension at 12 weeks of age, which was blocked by early sodium hydrosulfide administration. Concentrations of H2S were increased in the kidney in SHR + NaHS group versus WKY. Sodium hydrosulfide reduces mRNA expression of four H2S-generating enzymes and decreased 3-mercaptopyruvate sulphurtransferase protein level in SHRs. Early administration of sodium hydrosulfide decreases plasma NG monomethyl-l-arginine (l-NMMA, an inhibitor of NO synthase) level and increases plasma NO level in SHRs. Next, sodium hydrosulfide administration reduces renal mRNA expression of Ren, Atp6ap2, Agt, Ace, and Agtr1a in SHRs. We conclude that early short-term sodium hydrosulfide treatment increases renal H2S concentrations, restores NO bioavailability, and blocks the RAS in the kidney, in favor of vasodilatation to prevent the development of hypertension in adult SHRs.

Associations of urinary sodium and sodium to potassium ratio with hypertension prevalence and the risk of cardiovascular events in patients with prehypertension.

The aim of this study was to investigate the effects of urinary sodium and sodium to potassium ratio on inflammatory cytokines, hypertension, and cardiovascular disease in patients with prehypertension. The authors observed 627 patients with prehypertension in the General Hospital of Shenyang Military Region. Rank correlation analysis revealed that interleukin 6 expression exhibited significant positive correlations with urinary sodium (R = .13) and sodium to potassium ratio (R = .13). The multivariate-adjusted hazard ratio of 24-hour urinary sodium was 1.01 (95% confidence interval, 1.00 - 1.01) for hypertension and 1.01 (95% confidence interval, 1.00 - 1.02) for cardiovascular disease, whereas the hazard ratio for 24-hour urinary sodium to potassium ratio was 1.13 (95% confidence interval, 1.08 - 1.19) for hypertension and 1.10 (95% confidence interval, 1.04 - 1.17) for cardiovascular disease. The study suggests that a high-salt diet may lead to increased interleukin 6 levels and may contribute to hypertension. In addition, a high sodium to potassium ratio and high sodium levels are associated with increased risks of cardiovascular disease and hypertension in patients with prehypertension.

Matrix metalloproteinase (MMP)-2 decreases calponin-1 levels and contributes to arterial remodeling in early hypertension.

Increased matrix metalloproteinase (MMP)-2 is implicated in the vascular remodeling of hypertension. Calponin-1 is a contractile protein, and its absence is associated with vascular smooth muscle cell (VSMC) phenotype switch, which leads to migration and remodeling. We evaluated whether increased MMP-2 activity precedes chronic vascular remodeling by decreasing calponin-1 and inducing VSMC proliferation. Sham or two kidney-one clip (2K1C) rats were treated with doxycycline at 30mg/kg/day. Systolic blood pressure was increased in the 2K1C rats after 1 and 2weeks post-surgery, and doxycycline was effective to reduce it only at 2weeks of hypertension (p<0.05). Increased activity of MMP-2 was observed in aortas from 2K1C at 1 and 2weeks of hypertension, followed by increased VSMC proliferation, and those effects were abolished by treating 2K1C rats with doxycycline (p<0.05). Increased aortic media to lumen ratio started to emerge in 2K1C rats at 1week of hypertension, and it was established by 2weeks. MMP-2 and calponin-1 co-localized in the cytosol of VSMC. Aortas from 2K1C rats showed a significant reduction in calponin-1 levels at 1week of hypertension, and doxycycline prevented its loss (p<0.05). However, at 2weeks of hypertension, calponin-1 was upregulated in 2K1C (p<0.05 vs. Sham groups). The mRNA levels of calponin-1 were not altered in the aortas of 2K1C at 1week of hypertension. MMP-2 may contribute to the post-translational decrease in calponin-1, thus culminating in hypertension-induced maladaptive arterial remodeling.

Polyphenols: a Promising Nutritional Approach to Prevent or Reduce the Progression of Prehypertension.

Diet plays a crucial role in maintaining healthy blood pressure. Functional foods are increasingly popular among health-conscious consumers to reduce cardiovascular risk factors and improve vascular health. In particular, dietary polyphenols represent an extraordinary inventory of structurally different compounds that may represent promising candidate chemical entities to prevent or delay the onset of hypertension. In recent years, it has been recognized that prehypertension may be a predictor of clinical hypertension and consequently of cardiovascular risk. Moreover, prehypertension status is associated with increased levels of several inflammatory markers and it is also characterized by structural changes, including endothelial dysfunction and arteriolar hypertrophy. Despite the low bioavailability of polyphenols and the lack of clinical data from nutritional intervention studies, the antihypertensive role of polyphenols to control blood pressure and reduce inflammation and endothelial dysfunction has been subject of recent debate. The purpose of this article is to discuss the potential benefits of dietary polyphenols as a promising and effective nutritional strategy for the management of prehypertension.

Pre-hypertension: Is it an inflammatory state?

Even though several studies have implicated the role of inflammation in the pathogenesis of hypertension and other cardiovascular disease, there are only limited studies about inflammatory markers in prehypertension. The objective of the present article was to review the role of markers like C-reactive protein, interleukin-6, tumor necrosis factor-α and sialic acid in prehypertension. An extensive literature search was made in Pubmed (http://www.ncbi.nlm.nih.gov/pubmed/) using phrases such as prehypertension, inflammation, C-reactive protein, cardiovascular disease, cytokines and sialic acid. Several investigators have reported increased inflammatory markers like C-reactive protein, interleukin-6, tumor necrosis factor-α and sialic acid in prehypertension indicating the role of inflammation in the pathogenesis of prehypertension and its complications. Elevated inflammatory markers may enhance the risk for cardiovascular disease in subjects with prehypertension.

Increased endothelial progenitor cells and nitric oxide in young prehypertensive women.

This study investigated the effect of sex differences on circulating endothelial progenitor cells (EPCs) in prehypertension and its underlying mechanism. The authors found that premenopausal women show increased number and activity of circulating EPCs when compared with men, which was similar to enhanced nitric oxide (NO) level in plasma or culture medium. There was no difference in the number and activity of circulating EPCs and NO level between normotensive and prehypertensive premenopausal women. There was also no difference seen in levels of vascular endothelial growth factor and granulocyte macrophage colony-stimulating factor. Both number and activity of circulating EPCs were correlated with the level of NO. The present study firstly demonstrated that the number and activity of circulating EPCs were preserved in prehypertensive premenopausal women, which was related to the restoration of NO production. The sex differences in EPCs in prehypertension may be involved in the mechanism underlying vascular protection in premenopausal women.

Association of cardiometabolic risk profile with prehypertension accompany hyperhomocysteinaemia.

BACKGROUND: Study suggested that elevated homocysteine showed a multiplicative effect on cardiovascular diseases in hypertensive subjects. It was reported that elevated homocysteine level was independently associated with increased arterial stiffness in prehypertensives. It remains unclear whether prehypertensives combined with elevated homocysteine have adverse cardiovascular risk factors. We aimed to compare cardiometabolic risk profile between prehypertensives with hyperhomocysteinaemia and those without either condition. METHODS: Plasma total homocysteine and risk profile were determined among 874 Chinese non-hypertension individuals in Tianjin. They were subdivided into four groups: prehypertension with hyperhomocysteinaemia (≥10 µmol/L), prehypertension with normal homocysteine (<10 µmol/L), normotension with hyperhomocysteinaemia, normotension with normol homocysteine, respectively. RESULTS: In 874 participants, 22.5% of them were male, mean age was 56.8 years. In multiple comparisons, after adjustment for age, gender, smoking, alcohol, exercise, education prehypertensives had higher body mass index (BMI) and high sensitive C reactive protein (hs-CRP) than normotensives (p < 0.05, respectively); Only prehypertensive subjects with hyperhomocysteinaemia had higher triglyceride and serum uric acid compared to normotensive subjects, and lower HDL cholesterol than normotensives with normal homocysteine (p < 0.05, respectively). However, the significance of higher hs-CRP, uric acid and lower HDL cholesterol were abolished when further adjustment was made for BMI. CONCLUSION: The combination of prehypertension and hyperhomocusteinaemia increases the likelihood of having adverse cardiometabolic risk profile. Strict lipid management and weigh control may be needed in prehypertensives with elevated homocysteine.

Na+/K+-ATPase ß1-subunit is recruited in Na-K-2Cl co-transporter isoform 2 multiprotein complexes in rat kidneys: possible role in blood pressure regulation.

OBJECTIVE: The progression from prehypertensive to hypertensive state in spontaneous hypertensive rats (SHRs) is accompanied by a significant increase in membrane expression of Na-K-2Cl co-transporter isoform 2 (NKCC2), suggesting that the altered NKCC2 trafficking and activity are directly related with the development of hypertension in this strain. The aim of this work is to gain insights on the molecular mechanism that underlies this phenomenon. METHODS: We performed a comparative analysis of NKCC2 multiprotein complexes (MPCs) in the kidney of SHRs versus Wistar Kyoto rats by Blue Native difference gel electrophoresis combined with mass spectrometry. RESULTS: We found that the recruitment of the ß-subunit isoform 1 of the Na(+)-K(+)-ATPase (ß1NK) in NKCC2 MPCs was significantly increased in the kidneys of SHR compared with Wistar Kyoto rat control strain. Co-immunoprecipitation experiments showed that ß1NK actually interacts with NKCC2 in the native tissue. The analysis of the physiological role of ß1NK-NKCC2 interaction in human embryonic kidney cells showed that ß1NK increased the steady-state membrane expression and activity of NKCC2 enhancing NKCC2 trafficking toward the plasma membrane. CONCLUSION: We identify a new NKCC2-interacting partner involved in the modulation of NKCC2 intracellular trafficking and possibly involved in the regulation of blood pressure.

Prehypertension-associated elevation in circulating lysophosphatidlycholines, Lp-PLA2 activity, and oxidative stress.

Prehypertension is a risk factor for atherosclerosis. We investigated alterations in plasma metabolites that are associated with prehypertension. A group of 53 individuals was identified who remained within the range of prehypertension during repeated measurements in a 3-year period. This group was compared with the control group of 53 normotensive subjects who were matched for age and gender. Metabolomic profiles were analyzed with UPLC-LTQ-Orbitrap mass spectrometry. The prehypertensive group showed higher levels of lysophosphatidylcholines (lysoPCs) containing C14:0, C16:1, C16:0, C18:2, C18:1, C18:0, C20:5, C20:4, C20:3, and C22:6, higher circulating Lp-PLA2 activity, oxidized LDL (ox-LDL), interleukin 6 (IL-6), urinary 8-epi-PGF2α, and higher brachial-ankle pulse wave velocity (ba-PWV), before and after adjusting for BMI, WHR, smoking, alcohol consumption, serum lipid profiles, glucose, and insulin. LysoPC (16:0) was the most important plasma metabolite for evaluating the difference between control and prehypertensive groups, with a variable important in the projection (VIP) value of 17.173, and it showed a positive and independent association with DBP and SBP. In the prehypertensive group, the levels of lysoPC (16:0) positively and significantly correlated with ox-LDL, Lp-PLA2 activity, 8-epi-PGF2α, ba-PWV, and IL-6 before and after adjusting for confounding variables. Prehypertension-associated elevations in lysoPCs, Lp-PLA2 activity, ox-LDL, urinary 8-epi-PGF2α, IL-6, and ba-PWV could indicate increased oxidative stress from Lp-PLA2-catalyzed PC hydrolysis during increased LDL oxidation, thereby enhancing proinflammation and arterial stiffness.

Uric acid metabolism in pre-hypertension and the metabolic syndrome.

In humans uric acid (UA) is the end product of degradation of purines. The handling of UA by the renal system is a complex process which is not fully understood. To date, several urate transporters in the renal proximal tubule have been identified. Among them, urate transporter 1 (URAT1) and a glucose transporter 9 (GLUT9) are considered of greater importance, as potential targets for treatment of hyperuricemia and the potential associated cardio-metabolic risk. Therefore, the recognition of the metabolic pathway of UA and elucidation of occurrence of hyperuricemia may provide important insights about the relationship between UA, pre-hypertension (preHT) and the metabolic syndrome (MetS). We also review the available clinical studies in this field, including experimental studies dealing with the mechanisms of UA transport via different transporters, as well as current treatment options for hyperuricemia in patients with MetS, preHT or cardiovascular risk factors.

Uric acid reduction rectifies prehypertension in obese adolescents.

Epidemiologic studies, animal models, and preliminary clinical trials in children implicate uric acid in the development of essential hypertension. Controversy remains as to whether the observations indicate a general mechanism or a surrogate phenomenon. We sought to determine whether uric acid is a causative mediator of increased blood pressure (BP) and impaired vascular compliance. We report a randomized, double-blinded, placebo-controlled trial comparing 2 mechanisms of urate reduction with placebo in prehypertensive, obese, adolescents, aged 11 to 17 years. Subjects were randomized to the xanthine oxidase inhibitor, allopurinol, uricosuric, probenecid, or placebo. Subjects treated with urate-lowering therapy experienced a highly significant reduction in BP. In clinic systolic BP fell 10.2 mm Hg and diastolic BP fell 9.0 mm Hg in treated patients compared with a rise of 1.7 mm Hg and 1.6 mm Hg systolic and diastolic BP, respectively in patients on placebo. Urate-lowering therapy also resulted in significant reduction in systemic vascular resistance. These data indicate that, at least in adolescents with prehypertension, uric acid causes increased BP that can be mitigated by urate lowering therapy.

Decreased erythrocyte NA+,K+-ATPase activity and increased plasma TBARS in prehypertensive patients.

The essential hypertension has been associated with membrane cell damage. The aim of the present study is investigate the relationship between erythrocyte Na(+),K(+)-ATPase and lipoperoxidation in prehypertensive patients compared to normotensive status. The present study involved the prehypertensive patients (systolic: 136 ± 7 mmHg; diastolic: 86.8 ± 6.3 mmHg; n = 8) and healthy men with normal blood pressure (systolic: 110 ± 6.4 mmHg; diastolic: 76.1 ± 4.2 mmHg; n = 8) who were matched for age (35 ± 4 years old). The venous blood samples of antecubital vein (5 mL) were collected into a tube containing sodium heparin as anticoagulant (1000 UI), and erythrocyte ghosts were prepared for quantifying Na(+),K(+)-ATPase activity. The extent of the thiobarbituric acid reactive substances (TBARS) was determined in plasma. The statistical analysis was carried out by Student's t-test and Pearson's correlation coefficient. A P < 0.05 was considered significant. The Na(+),K(+)-ATPase activity was lower in prehypertensive patients compared with normotensive subjects (4.9 versus 8.0 nmol Pi/mg protein/min; P < 0.05). The Na(+),K(+)-ATPase activity correlated negatively with TBARS content (r = -0.6; P < 0.05) and diastolic blood pressure (r = -0.84; P < 0.05). The present study suggests that Na(+),K(+)-ATPase activity reduction and elevation of the TBARS content may underlie the pathophysiological aspects linked to the prehypertensive status.

Effect of dark chocolate on nitric oxide serum levels and blood pressure in prehypertension subjects.

AIM: to investigate the effect of consumption of dark chocolate 30 g/day for fifteen days on Nitric oxide (NO) serum levels and blood pressure in male and female employees with prehypertension. METHODS: the study was a parallel randomized clinical trial. A total of thirty-two subjects was divided into two groups using block randomization. Sixteen subjects received 30 g/day dark chocolate and dietary counseling (treatment group) and the other 16 subjects received white chocolate 25 g/day and dietary counseling (control group) for fifteen days. Data collected in this study consisted of age, physical activity, body massa index, intake of energy, intake of sodium, and intake of polyphenol, NO serum levels and blood pressure. The measurement of NO serum levels was done in pre- and after- treatment, while blood pressure was assessed in pre- , during- and after- treatment. Statistical analysis was performed using independent t-test for normal distribution data and Mann-Whitney test for not normal distribution data, with the level of significancy of 5%. RESULTS: after 15 days treatment, NO serum level between treatment and control groups were significantly different 7.70 ± 3.84 vs 1.92(-0.79 ± 17.78) (p=0.001). Both groups had decreased systolic and diastolic blood pressure. Systolic blood pressure was different significantly between groups after treatment 120.64 ± 8.47 vs 131.19 ± 7.45 (p=0.001), while diastolic blood pressure was not significant 74.14 ± 6.30 vs 77.44 ± 10.29 (p=0.308). CONCLUSION: in prehypertension subjects, dark chocolate 30 g/day increased NOx serum levels and decreased systolic blood pressure after 15 days of treatment.

Oxidized low-density lipoprotein, angiotensin II and increased waist cirumference are associated with valve inflammation in prehypertensive patients with aortic stenosis.

INTRODUCTION: The progression of aortic stenosis (AS) has been shown to be faster in patients with the metabolic syndrome. We sought to determine the relationships between blood pressure, inflammation, oxidative stress and valvular inflammation in a population of normotensive and prehypertensive patients with AS. METHODS: In this study, 36 male patients (age: 61.5±2 years) with AS undergoing an aortic valve replacement were investigated. Plasma levels of adiponectin, oxidized-LDL (ox-LDL), angiotensinogen (AGN) and angiotensin I-II (Ang I-II) were measured. On explanted aortic valves, immunohistochemistry studies and quantitative PCR (q-PCR) analyses were performed to document the expression of inflammatory cytokines. RESULTS: Systolic blood pressure (SBP) was positively correlated with plasma level of ox-LDL (r=0.4; p=0.02), AGN (r=0.41; p=0.01), and white blood cells count (r=0.33; p=0.04), whereas it was inversely related to plasma level of adiponectin (r=-.35; p=0.04). After adjustment for covariates, plasma level of ox-LDL (p=0.01) remained significantly associated with SBP (p=0.01). Within the aortic valve, expression of TNF-α was significantly associated with plasma levels of ox-LDL (r=0.58; p=0.03), Ang II (r=0.69; p=0.013), and waist circumference (r=0.60; p=0.02), whereas valvular expression of IL-6 was associated with plasma level of Ang II (r=0.51; p=0.03). In explanted AS valves, ox-LDL was documented near calcified areas and colocalized with Ang II, IL-6, and TNF-α. CONCLUSION: Conditions associated with a higher oxidative stress and activation of the renin angiotensin system, such as encountered in viscerally obese and prehypertensive patients, contribute to higher valvular inflammation in AS.