bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 005: Hemodynamic and Renal Changes in Obese Patients 12 Months After Bariatric Surgery
Authors: Oliveras Anna , Granados Ana M , Alvarez Sara , Goday Albert , Sans Laia , Vazquez Susana , Faura Anna , Pascual Julio
Published: December 2018

Aim:
to study changes in central and peripheral 24h-BP, as well as in estimated glomerular filtration rate (eGFR) and albuminuria (Alb), 12 months after bariatric surgery (BS).

Methods:
Sixty-two patients (39% hypertensives) with severe obesity (BMI 42.7±5.6 Kg/m
2
) were evaluated prospectively before (0) and 1,3,6 and 12 months after undergoing BS. Peripheral and central BP parameters were determined by the Mobil-O-Graph device. Renal function was evaluated by eGFR and Alb. Generalized estimation equations were used to evaluate repeated measures in the variables analyzed.

Results:
at 12 months weight (-35.7±9.9 Kg) and waist circumference (-27 ± 9.2 cm) decreased (p<0.001 for both). The Table shows a significant decrease in only systolic BP, in both the 24h and daytime periods, but not in the nocturnal period. There was a decrease in plasma aldosterone (Ald) levels (mean,95%CI: -36.7 pg/mL, -60 to -13.4, p=0.003). After adjusting for age, BP
0
, variation (Δ) of weight, Δ Ald and having or not HT at baseline, the only significant covariables in Δ 24h-SBP and Δ day-SBP were previous HT and Δweight. There was a decrease in eGFR (mean,95%CI: -5.6 mL/min/1.73m
2
, -9.4 to -1.8, p=0.005) and Alb (Z=-2.04,p=0.042). According to the constructed variance analysis models, the Δ Alb was dependent on Alb
0
and on Δ night-SBP, but not on the baseline hypertensive state, on the Δ eGFR nor on the Δweight (adjusted r
2
=0.606). Δ eGFR was independent of baseline eGFR and Δ weight.

Conclusions:
patients with morbid obesity significantly reduce heart rate and 24h- and day- SBP, both central and peripheral, 12 months after undergoing BS. In addition, there is a significant decrease in plasma Ald, eGFR and Alb.
Abstract 006: A Dual Role of 12/15-lipoxygenase in Lipopolysaccharide-Induced Acute Renal Inflammation and Injury
Authors: Elmarakby Ahmed A , Ibrahim Ahmed S , Katary Mohamed A , Abd El Razek Ahmed M , Elsherbini Nehal M , Al-Shabrawey Mohamed
Published: December 2018

Recent studies suggest a potential role of bioactive lipids in lipopolysaccharide (LPS) induced acute kidney injury. The current study was designed to determine the profiling activities of various polyunsaturated fatty acid (PUFA) metabolizing enzymes, including lipoxygenases (LO), cyclooxygenase and cytochrome P450 in the plasma of LPS-injected C57BL/6 mice (4 mg/kg i.p) using LC-MS. Heat map analysis revealed that out of 126 bioactive lipids screened, only the 12/15-LO metabolite, 12-HETE, had a significant (2.24 ± 0.4) fold increase relative to control (P= 0.0001). We then determined the role of the 12/15-LO in LPS-induced acute kidney injury using genetic and pharmacological approaches. Treatment of LPS injected mice with the 12/15-LO inhibitor, baicalein significantly improved creatinine clearance (0.05±0.01 ml/min in baicalein treated vs. 0.02±0.004 ml/min in untreated LPS injected mice) and reduced albumin to creatinine ratio (54±18 μg/mg in baicalein treated vs. 143±31 μg/mg in untreated LPS injected mice) in LPS injected mice. Baicalein treatment significantly reduced markers of renal inflammation {urinary thiobarbituric acid reactive substance (TBARs), urinary monocyte chemoattractant protein-1 (MCP-1), renal intercellular adhesion molecule 1 (ICAM-1), and tumor necrosis factor-α (TNF-α) levels}. Knocking-out of 12/15-LO also reduced markers of renal inflammation and injury elicited by LPS injection. Next, we sought to divert the role of 12/15-LO from being pro-inflammatory to anti-inflammatory via dietary supplementation with docosahexaenoic acid (DHA) and generation of anti-inflammatory metabolite, resolvin D2 (RvD2). DHA-treatment significantly reduced marker of renal injury and inflammation in LPS-injected mice whereas DHA treatment failed to provide any synergistic effects in reducing renal inflammation and injury in LPS injected 12/15-LO knock-out mice by increasing plasma RvD2 levels. This was further confirmed by exogenous RvD2 administration which significantly reduced the elevation in renal injury and inflammation in LPS injected mice. In conclusion, our data suggest a double-edged sword role of 12/15-LO in LPS-induced acute renal injury, depending on the type of substrate available for its activity.
Abstract 009: Regulatory Role of Endothelial Sirt3 on Blood Pressure and Diastolic Dysfunction in a Female Mice
Authors: Zeng Heng , Worsham Rebecca A , Chen Jian Xiong
Published: December 2018

Heart failure with preserved ejection fraction (HFpEF) accounts for almost one half of the heart failure population which is characterized by a diastolic dysfunction. HFpEF is strongly associated with advanced age and metabolic comorbidities as well as endothelial dysfunction. Sirt3 emerged as a protein of particular interest to the aging due to its association with long lifespans in humans. SIRT3KO mice have decreased time to development of age-related diseases. Diastolic dysfunction is increasingly prevalent in aged women. Clinical studies have shown that obese and diabetic women are more likely to develop diastolic dysfunction than their male counterparts. Our study showed that ablation of endothelial Sirt3 led to diastolic dysfunction in male mice. However, the role of endothelial SIRT3 deficiency on blood pressure and diastolic function in female mice remains to be investigated. In the present study, we demonstrate that ablation of endothelial SIRT3 in females led to an increase in blood pressure as compared with control SIRT3 LoxP female mice. Diastolic function measurement also showed that IVRT and MPI were significantly increased whereas E’/A’ ratio was reduced in the SIRT3
EC
KO female mice. To further investigate the regulatory role of endothelial SIRT3 on blood pressure and diastolic dysfunction in metabolic stress, SIRT3
EC
KO female mice and SIRT3 LoxP female mice were fed with normal diet and high-fat diet (HFD) for 16 weeks. Knockout of endothelial SIRT3 resulted in an increased blood pressure in female mice fed with HFD. Intriguingly, Sirt3
EC
KO female mice + HFD exhibited impaired coronary flow reserve (CFR) and more serve diastolic dysfunction as evidence elevated IVRT as compared with control SIRT3 LoxP female mice + HFD. In addition, female SIRT3
EC
KO mice had higher blood pressure and diastolic dysfunction as compared to male SIRT3
EC
KO mice. Moreover, female SIRT3
EC
KO mice + HFD had an impaired CFR and diastolic dysfunction as compared to male SIRT3
EC
KO mice + HFD. These results implicate a sex different role of endothelial SIRT3 in regulating blood pressure and diastolic function in mice. Deficiency of endothelial SIRT3 may be responsible for a diastolic dysfunction in aging female.
Abstract 017: Effect of Sildenafil on Nitric Oxide-Mediated Vasodilation in the Human Placenta: an Ex-Vivo Placental Perfusion Study
Authors: Hitzerd Emilie , Glisic Marija , Colafella Katrina M , de Vries René , Schoenmakers Sam , Merkus Daphne , Reiss Irwin K , Danser A H , Simons Sinno H
Published: December 2018

Preeclampsia (PE) is a serious pregnancy complication characterized by suboptimal placentation, leading to increased vascular resistance and generalized endothelial dysfunction. A promising treatment is sildenafil, a phosphodiesterase-5 (PDE5) inhibitor that enhances nitric oxide (NO) mediated vasodilation. Although there are currently sildenafil trials ongoing in pregnant women, the effects of sildenafil on the placenta are still unknown. Placentas of healthy (n=17), early-onset (Eo)PE (n=6) and late-onset (Lo)PE (n=5) pregnancies were dually perfused, pre-constricted with serotonin, and subsequently exposed to the NO donor SNP in the absence or presence of 1 μmol/L sildenafil. Two healthy placentas were perfused with sildenafil on the maternal side to study placental transfer. Placental protein expression of PDE5, PDE1A, eNOS and iNOS was assessed using Western blot. Mean baseline pressure ±SEM was significantly lower (p<0.05) in EoPE (22.3±2.8 mmHg) and LoPE (22.8±1.7 mmHg) vs. healthy placentas (33.1±2.2 mmHg). There was no effect of sildenafil on baseline pressure or serotonin-induced pre-constriction. Sildenafil tended to enhance vasodilatory response to 10
-6
M SNP in healthy (mean pressure decrease 4.3±0.8 vs. 8.1±1.9 mmHg, p=0.1) and LoPE placentas (3.0±1.0 vs. 7.3±3.2 mmHg), while no improvement was seen in EoPE placentas (6.0±2.0 vs. 5.0±1.0 mmHg). When sildenafil was added at the maternal side, average fetal-maternal concentration ratio was 0.22 after 3 hours of perfusion, as compared to 0.86 for antipyrine, a freely diffusing molecule. Placental levels of PDE1A tended to be higher in PE (p=0.08), while no differences in expression of PDE5, eNOS and iNOS were observed between PE and healthy placentas. Our study reveals that PE placentas have a significantly lower baseline pressure compared to healthy placentas, possibly due to lower resistance in the feto-placental vasculature as a compensation mechanism for the increased resistance in the spiral arteries. Although sildenafil tended to enhance vasodilation in healthy and LoPE placentas, it did not have those beneficial effects in EoPE. Possibly PDE1A-selective inhibitors should be applied in PE, or PDE is not the appropriate target for restoring disturbed vasodilation.
Abstract 018: High Stillbirth Rate and Altered Maternal Renal Function and Water Balance are Associated With Spontaneous Gestational Hypertension in Nonhuman Primates
Authors: Weaver Chelsea C , Louard Frances , Osborn Jeffrey L
Published: December 2018

Gestational hypertension (GH) is new-onset hypertension specific to pregnancy (PG) that may precede preeclampsia (PE). While the specific etiology of PE is unclear, defective fluid and electrolyte balances have been implicated. The African Green Monkey (AGM;
Chlorocebus aethiops sabaeus
) is a novel model of spontaneous GH with pathophysiological consequences of PE. Systolic blood pressure (SBP; forearm plethysmography) was measured in AGMs pre-PG, during each trimester, and postpartum (PP). Gestational age was estimated by fetal lengths at 7 weeks/trimester (21 week gestation). Animals were characterized as normotensive (NT; SBP < 120 mmHg in PG and PP) or gestational hypertensive (GH; SBP ≥ 140 mmHg during PG). SBP was unchanged in NT PG (pre-PG 110 ± 5 mmHg; 1
st
trimester 101± 6 mmHg; 3
rd
107 ± 7 mmHg; n = 27). In GH AGMs, SBP increased in the 3
rd
trimester from 115 ± 6 mmHg (1
st
) and 117 ± 25 mmHg (2
nd
) to 152 ± 7 mmHg (3
rd
; p<0.05; n = 16). Plasma osmolality did not change during PG for NT AGMs but declined in GH (NT pre-PG 305 ± 5 mOsm/kg; PG 299 ± 5 mOsm/kg; n = 6; GH pre-PG 313 ± 6; PG 293 ± 4 mOsm/kg; p<0.05 ANOVA; n = 15). Maternal body weight increased in GH by the 1
st
trimester, while NT body weight did not change until the 3
rd
trimester (NT pre-PG 3.8 ± 0.2 kg; 1
st
trimester 3.8 ± 0.3 kg; 3
rd
4.4 ± 0.2 kg; GH pre-PG 3.7 ± 0.1 kg; 1
st
trimester 4.4 ± 0.2 kg; 3
rd
4.7 ± 0.1 kg; p<0.05). Protein excretion was unchanged in NT AGMs but increased with GH compared to pre-PG and NT PG (NT pre-PG 365 ± 45 mg/day; 3
rd
trimester 466 ± 84 mg/day; GH pre-PG 346 ± 138 mg/day; 3
rd
trimester 702 ± 69 mg/day; p<0.05). Third trimester estimated GFR (eGFR) did not change in NT AGMs but declined in GH (NT 5.0 ± 0.7 ml/min vs GH 2.5 ± 0.5 ml/min; p<0.05). Infants from GH pregnancies were smaller (NT 327.4 ± 13.7 g, n = 5, vs GH 290.0 ± 8.5 g n = 15; p<0.05) and GH increased fetal stillbirth rate to 40% (6/15). Thus, GH in AGMs has early PG water retention, decreased plasma osmolality and excess weight gain preceding GH. GH AGMs have smaller infants and increased stillbirth rates, showing fetal growth restriction. Elevated SBP during GH may lead to renal dysfunction, proteinuria and reduced eGFR. Thus, the AGM is a novel, translational model of hypertensive pregnancy disorders for the study of acute and long-term effects on fetal development.
Abstract 019: A20 in Dendritic Cells Protects Against Hypertension by Inhibiting Dendritic Cell-Mediated T Cell Activation
Authors: Lu Xiaohan , Rudemiller Nathan , Zhang Jiandong , Privratsky Jamie , Hammer Gianna , Zhang Joyce , Wen Yi , Ren Jiafa , Crowley Steven D
Published: December 2018

The ubiquitin-editor protein A20 in dendritic cells (DCs) suppresses NF-κB signaling and inhibits their capacity to activate T cells by limiting DC expression of co-stimulatory molecules. We previously reported that mice with spontaneous DC activation due to heterozygous deletion of A20 in DCs (CD11c-cre+ A20
flox/wt
= DC ACT) have an exaggerated hypertensive response to low dose (300 ng/kg/min) chronic angiotensin (Ang) II infusion (143±2 vs. 131±4 mmHg; p=0.04) and augmented proportions of effector T cells in the kidney lymph node. Here, we explored the mechanism through which A20 in DCs limits blood pressure elevation. After 7 days of chronic Ang II infusion, flow cytometric analysis of kidney homogenates from wild-type (WT = CD11c-cre
-
A20
flox/wt
) and DC ACT mice revealed similar numbers of renal DCs in the 2 groups (2832±342 vs. 2531±435; p=NS). By contrast, numbers of CD11b
+
Ly6C
hi
inflammatory monocytes (9849±1108 vs. 6019±597; p=0.01) and CD8
+
T cells (1757±101 vs. 908±155; p<0.03) were increased in the DC ACT kidneys compared to WT controls. Accordingly, the DC ACT kidneys showed upregulated mRNA expression for the pro-hypertensive cytokines TNF-α (1.6±0.2 vs. 1±0.2; p<0.02) and IL-17A (2.3±0.6 vs. 1±0.3; p=0.09) and the mononuclear cell chemokine CCL5 (1.9±0.27 vs. 1±0.11; p=0.01). Both monocytes and T cells have been implicated in the pathogenesis of hypertension. Therefore, to directly test whether enhanced T cell activation in the DC ACT cohort was responsible for their augmented hypertensive response, we chronically infused Ang II into lymphocyte-deficient DC ACT Rag1
-/-
mice and WT (CD11c-cre- A20
flox/wt
) Rag1
-/-
controls for 4 wks. In WT Rag1
-/-
and DC ACT Rag1
-/-
mice, radiotelemetry blood pressures (128±1 vs. 128±2 mmHg; p=NS) and heart to body weight ratios (6.0±0.1 vs. 6.4±0.2 mg/g body wt) were similar during Ang II, suggesting that T cells are required to mediate the augmented hypertensive response accruing from DC activation due to A20 deficiency. Thus, following stimulation of the renin angiotensin system, A20 suppresses DC activation and thereby mitigates T cell-dependent blood pressure elevation. These studies identify a novel target through which to limit the engagement of adaptive immunity during chronic hypertension.
Abstract 020: Sex Difference in T Regulatory Cells After Adoptive Transfer From Hypertensive Donors Leads to Protection Against T Cell-Mediated Hypertension in Premenopausal Female Mice
Authors: Pollow Dennis P , Sylvester Megan A , Husband Nathaniel A , Uhlorn Joshua A , Romero-Aleshire Jill , Uhrlaub Jennifer , Nikolich-Zugich Janko , Brooks Heddwen L
Published: December 2018

Activation of T cell-dependent pro-inflammatory responses are required for Ang II hypertension in male mice. However, females are protected from T cell-mediated hypertension and may suppress hypertension by directly preventing Ang II-induced pro-inflammatory T cell activation. Here we sought to determine whether transferring T cells from hypertensive donor mice eliminates female protection against T cell-mediated hypertension. Splenic CD3
+
T cells were transferred from normotensive (NT) or Ang II-hypertensive (HT) C57BL/6J male donors to female Rag-1
-/-
(NT T cell female-NTF; HT T cell female-HTF) or male Rag-1
-/-
(HT T cell male-HTM) recipient mice. Blood pressure was monitored (tail cuff) for 5 weeks post-transfer. Ang II (490ng/kg/min) was infused into recipient mice for 14 days during weeks 4 and 5 post-transfer (NTFA; HTFA; HTMA). Ang II significantly increased MAP in donor male mice (NT 114 vs HT 157 mmHg, p<0.05). Transfer of T cells from HT donors did not induce HT in female or male recipients. Similarly, T cell donor environment did not affect Ang II-induced blood pressure in female recipients, which remained protected compared to male recipients (MAP: NTF 83
+
4 mmHg*, HTF 88
+
6 mmHg*, NTFA 101
+
5 mmHg*, HTFA 103
+
5 mmHg*, HTMA 138
+
3 mmHg, *p<0.05 vs HTMA). Flow cytometry demonstrated similar splenic T cell frequency across all groups (CD3: NTF 18%, NTFA 16%, HTF 17%, HTFA 14%, HTMA 18%, p>0.05). However, regulatory T cells were significantly reduced in male recipients compared to all female groups (Foxp3: NTF 21.6%*, NTFA 22.2%*, HTF 22.8%*, HTFA 22.6%*, HTMA 15.3%, *p<0.05 vs HTMA) Females had significantly less renal T cell infiltration compared to males and infiltration was not impacted by Ang II infusion or T cell donor status (CD3: NTF 12,083*, NTFA 11,317*, HTF 12,656*, HTFA 8,997*, HTMA 22,405, *p<0.05 vs HTMA; CD4: NTF 6,411*, NTFA 4,702*, HTF 5,831*, HTFA 4,579*, HTMA 9,914, *p<0.05 vs HTMA; CD8: NTF 5,397*, NTFA 6,123*, HTF 6,362*, HTFA 3,792*, HTMA 11,727, *p<0.05 vs HTMA). These results demonstrate that female mice prevent T cell-mediated hypertension and renal T cell infiltration regardless of previous T cell exposure to a hypertensive environment, suggesting a direct preventive mechanism in females against pro-hypertensive T cell responses.
Abstract 022: Proteasome Inhibition Prevents Renal Inflammation and Hypertension by Abrogation of Dendritic Cell Autoantigen Presentation
Authors: Patrick David M , Xiao Liang , Chen C. W , Ao Mingfang , Kirabo Annet , Harrison David G
Published: December 2018

Reactive oxygen species (ROS) have been shown to be important mediators of hypertension. Isolevuglandins (isoLG) are oxidation products of fatty acids that adduct to lysine residues of proteins. Our prior data suggest that isoLG-adducted proteins are presented by dendritic cells (DCs) and activate T-cells resulting in hypertension. Identification of the source and mechanism of presentation of isoLG adducts is critical for the development of therapies targeting this process. Antigens formed intracellularly are processed by the proteasome and presented to CD8
+
T cells in MHC class I (MHC-I). We hypothesize that within DCs, isoLG-adducted peptides are processed by the proteasome and presented in MHC-I. Treatment of mouse DCs with the oxidant tert-butyl hydroperoxide (TBHP) increased levels of isoLG-adducts on the DC surface, as detected by flow cytometry, from 1.3 x 10
3
to 11.4 x 10
3
/10
6
DCs (N = 9, P < 0.01). Co-treatment of mouse DCs with TBHP and proteasome inhibitors (PIs) bortezomib (BTZ) or MG132 attenuated surface isoLG-adduct levels when compared to TBHP alone (2.7 x 10
3
or 3.5 x 10
3
vs 11.4 x 10
3
/10
6
DCs, N = 9, P < 0.001). Moreover, using flow cytometry-based fluorescence resonance energy transfer, we found that isoLG-adducted peptides and MHC-I interact at the intermolecular level on mouse DCs, suggesting that IsoLG-modified peptides are presented within MHC-I. Co-treatment of these cells with TBHP and BTZ attenuated this interaction compared with TBHP treatment alone (2.9 x 10
3
vs 32.7 x 10
3
/10
6
DCs, N = 9, P < 0.001). Next, mice were treated with angiotensin II (ang II) with or without co-treatment with BTZ. Co-treated animals exhibited reduced mean systolic blood pressure (161.7 ± 7.2 vs 122.9 ± 17.9 mmHg, N = 4-5, P < 0.05) and a reduction in renal macrophages (13.4 x 10
3
vs 6.57 x 10
3
DCs/Kidney, N = 4-5, P < 0.001) and DCs (129.4 x 10
3
vs 79.9 x 10
3
DCs/Kidney, N = 4-5, P < 0.05). These studies provide evidence that the proteasome processes isoLG adducts into peptides that are presented within MHC -I, and that proteasome inhibitors can not only block this process, but in doing so, can reduce renal inflammation and lower blood pressure. Efforts to inhibit processing and presentation of isoLG-modified peptides may therefore have therapeutic benefit in hypertension.
Abstract 027: Hyperglycemia and Oxidative Stress Contribute to Impaired CerebralAutoregulation in Association With Dementia in Diabetes
Authors: Wang Shaoxun , He Xiaochen , Booz George , Roman Richard , Fan Fan
Published: December 2018

Diabetes mellitus is characterized by hyperglycemia and is well established to associate with oxidative stress. The present study examines whether impaired myogenic response of middle cerebral artery MCA and autoregulation of cerebral blood flow (CBF) in our T2DN diabetic rats is due to hyperglycemia and oxidative stress induced actin cytoskeleton reorganization, and if this contributes to dementia. We identified that both young (4-month) and older (18-month) T2DN diabetic rats exhibit impaired pressure-induced myogenic response in isolated MCAs. Forced dilatation occurred at pressures above 140 mmHg in MCAs isolated from elderly T2DN rats with mild hypertension but not controls. Cortical blood flow measured by laser Doppler flowmetry rose by 137 ± 15% and 36 ± 5%, respectively, in T2DN and SD rats when MAP was increased from 100 to 180 mmHg. Autoregulation of CBF was shifted to lower pressures in elderly T2DN rats and they exhibited breakthrough at pressures above 140 mmHg. The F-Actin distribution area was significantly reduced in the vascular smooth muscle cells (VSMCs) freshly isolated from MCAs of T2DN rats compared with normal Sprague Dawley (SD) rats. The F-actin was disrupted similarly in VSMCs treated with high glucose or H
2
O
2
. Superoxide production is elevated in fresh isolated middle cerebral arteries (MCA) in T2DN diabetic rats compared to normal SD rats. We also found increased production of superoxide in primary VSMCs isolated from normal SD rats cultured in high glucose condition or freshly isolated from diabetic rats. T2DN rats exhibited neurons death in the hippocampus and cortex. Elderly T2DN rats showed memory disabilities. These results indicate that hyperglycemia induced elevated superoxide production causes actin cytoskeleton reorganization in cerebral VSMCs of diabetic T2DN rats, which may contribute to impaired cerebral vascular function, neurodegeneration and cognitive impairment.
Abstract 041: Brain Cytochrome P450 1B1-Testosterone Generated Metabolite 6Beta-Hydroxytestosterone Contributes to Angiotensin II-Induced Increased Sympathetic Outflow and Blood Pressure
Authors: Singh Purnima , Oh SaeRam , Dutta Shubha Ranjan , Song Chi Young , Malik Kafait U
Published: December 2018

Cytochrome P450 1B1 (CYP1B1)-generated testosterone (T) metabolite 6β-hydroxytestosterone (6β-OHT) contributes to angiotensin (Ang) II-induced hypertension in the male mice. However, the site of action of CYP1B1-testosterone metabolite 6β-OHT in Ang II-induced hypertension is unknown. The demonstration that Ang II increases blood pressure by its action in the subfornical organ and the presence of CYP1B1 in the brain led us to hypothesize that T contributes to Ang II-induced hypertension via its metabolism to 6β-OHT in the brain. To test this hypothesis, we examined the effect of intracerebroventricularly (ICV) administered T in castrated (Cas) wild-type (
Cyp1b1
+/+
) and Cas
Cyp1b1
-/-
mice on the action of systemic Ang II (700 ng/kg/min) for 14 days. T (3 μg/2μL/injection/every 2nd day) or its vehicle (2-Hydroxypropyl-β-cyclodextrin dissolved in artificial CSF) was injected via a cannula implanted in the brain. Mean arterial blood pressure (MAP, mmHg) was measured by radiotelemetry (n=4-5). Ang II increased MAP in T but not its vehicle-injected Cas
Cyp1b1
+/+
mice on Day 12 (159±2 vs. 98±2, P<0.05). In Cas
Cyp1b1
-/-
mice Ang II increased MAP in ICV injected 6β-OHT (1.5 μg/2μL/injection every 2nd day) but not T (151±3 vs. 123±5, P<0.05). Power spectral analysis of the data on day 12 showed that Ang II increased the low to high-frequency ratio of heart rate variability, index of sympathetic outflow modulation in ICV T injected Cas
Cyp1b1
+/+
but not Cas
Cyp1b1
-/-
mice (3.8±0.0.4 vs. 1.9±0.0); whereas ICV 6β-OHT in the later mice increased this ratio (4.7±0.6). Ganglionic blocker hexamethonium (30 mg/Kg, ip) on day 14 of Ang II infusion resulted in greater reduction in MAP (P<0.05) in centrally 6β-OHT injected Cas
Cyp1b1
-/-
, and T-injected Cas
Cyp1b1
+/+
(Δ81±11 and Δ87±10) than in T injected Cas
Cyp1b1
-/-
mice (Δ50±8). Furthermore, in intact
Cyp1b1
-/-
, but not Cas
Cyp1b1
-/-
mice transduction with adenovirus (Ad) of CYP1B1-DNA (ICV 2μL of 1.0 X 10
12
particles/mL) increased Ang II-induced systolic blood pressure (P<0.05, n=5/group) measured by tail-cuff on Day12 (176±11 vs. 120±2, mm Hg). These data suggest that T contributes to Ang II-induced hypertension most likely via generation by the brain CYP1B1 to 6β-OHT, which increases sympathetic outflow in male mice.
Abstract 044: Purinoceptor-Dependent Regulation of Sodium Excretion is Sexually Dimorphic
Authors: Gohar Eman Y , Kasztan Malgorzata , Zhang Shali , Inscho Edward W , Pollock David M
Published: December 2018

Premenopausal women have a lower risk of hypertension compared to age-matched men. Recently, prominent roles have been assigned to P2Y
2
and P2Y
4
purinoceptor subtypes in promoting Na
+
excretion, implicating dysfunction of these receptors as potential contributors to hypertension. We recently reported that activation of P2Y
2
and P2Y
4
receptors in the renal medulla by UTP promotes Na
+
excretion in male rats. In intact females, UTP did not stimulate Na
+
excretion while ovariectomy unmasked UTP-induced natriuresis. These observations led us to hypothesize that intact females have higher basal renal medullary activity of P2Y
2
and P2Y
4
receptors in regulating Na
+
excretion compared to male and ovariectomized (OVX) rats. To test that, we determined (i) P2Y
2
and P2Y
4
mRNA and protein expression in the inner medulla from male, intact female and OVX Sprague Dawley rats and (ii) the effect of inhibiting medullary purinoceptors (P2 receptors) on Na
+
excretion in those rats. We found that P2Y
2
and P2Y
4
mRNA expression was higher in the inner medulla from females compared to males (1.00±0.09 vs. 0.70±0.05 and 1.00±0.22 vs. 0.29±0.05, respectively, P<0.5, n=5-10). These sex differences in P2Y
2
and P2Y
4
mRNA expression were eliminated by ovariectomy (0.60±0.06 and 0.29±0.04, respectively, p<0.5,n=5,8). Consistently, Western blots on inner medullary lysates showed that intact females have higher expression of P2Y
2
receptor, compared to males. In anesthetized rats, medullary P2 receptor inhibition by suramin (P2 receptor antagonist, 750 μg/kg/min) significantly attenuated Na
+
excretion in intact females (0.4±0.1 vs. 0.9±0.2 μmol/min, P<0.5, n=7), but not in male or OVX rats.To test whether estradiol (E
2
) increases the expression of P2Y
2
and P2Y
4
receptors, we subjected cultured mouse inner medullary collecting duct cells (mIMCD3) to different concentrations of E
2
(0, 10, 100 and 1000 nM). We found that E
2
dose-dependently increased the expression of P2Y
2
and P2Y
4
mRNA in mIMCD3. These data suggest that females have enhanced P2Y
2
and P2Y
4
-dependent regulation of Na
+
excretion in the renal medulla, compared to male and OVX rats, at least partially via an E
2
-dependent mechanism. This pathway may contribute to facilitated renal Na
+
handling in premenopausal females.
Abstract 045: Sox6 Has Protective Role During Renal Artery StenosisSInduced Hypertension
Authors: Saleem Mohammad , Xiao Liang , Horton Kandi , Hodgkinson Conrad P , Gomez Jose A
Published: December 2018

Introduction:
Renal artery stenosis is a common condition in patients with atherosclerosis. Narrowing of the renal arteries stimulate increases in renin production and release resulting in hypertension. Hypertension causes kidney injury and end organ damage. As such, there is much interest in developing novel treatments for the hypertension induced by renal artery stenosis. In renal artery stenosis, renin is a key disease driver. The objective of our study is to determine if the transcription factor Sox6 plays a role in renin induction of hypertension during renal artery stenosis.

Methods:
A novel transgenic mouse model (Ren1d
Cre
/Sox6
fl/fl
-Sox6KO) was used to determine the impact of specific Sox6 ablation in renin expression after different stimuli. Ten days of low sodium diet (0.01% Na) and furosemide (0.1 mg/g body weight) was used to induce JG cell expansion. 2 Kidney 1 Clip (2K1C) Goldblatt model was used as renal artery stenosis model. Blood pressure was measured by tail-cuff method.

Results:
In wild-type mice renin and Sox6 expression increased during JG cell expansion. However, specific Sox6 ablation in renin expressing cells halted the increase in the number of JG cells (8.75 fold decrease, n= 6 to 9, P= 0.001). Furthermore, Sox6 KO mice were protected from developing hypertension and kidney damage after renal artery stenosis. Systolic blood pressure (116±2.13 and 132.9±3.3, n=9-10) and mean arterial pressure (103.3±1.9 and 121.5±1.01, n=9-10) were significantly lower in Sox6 KO compared to wild-type mice. When stenosed kidneys were compared, renin expression was higher in wild-type compared to Sox6 KO group as measured by immunoblotting (0.49 ± 0.05898, and 0.2266±0.02716;
P
=0.0358, n=2-3). Creatinine levels in urine were higher in wild-type group compared to Sox6 KO group (2382 ± 399 and 1804 ± 177.8,
P
=0.0358, n=9).

Conclusion:
Our data indicates that Sox6 plays a novel role in modulating renal renin expression during pathological conditions. These results suggest that Sox6 is a potential drug target for therapies which seek to control blood pressure in hypertensive patients.
Abstract 060: Mitochondrial Deacetylase Sirt3 in Endothelial and Smooth Muscle Cells Protects From Vascular Dysfunction and Attenuates Hypertension
Authors: Dikalova Anna , Pandey Arvind , Xiao Liang , Itani Hana , Sidorova Tatiana , Verdin Eric , Auwerx Johan , Harrison David G , Dikalov Sergey I
Published: December 2018

Vascular dysfunction plays a key role in the development of hypertension and heart disease which causes one-third of deaths worldwide. Cardiovascular disease risk factors reduce mitochondrial deacetylase Sirt3 and Sirt3 declines with age paralleling the increased incidence of cardiovascular disease and hypertension; however, the role of Sirt3 was largely ignored. We hypothesized that Sirt3 plays critical role in vascular dysfunction and hypertension. To test this hypothesis we have developed novel tamoxifen-inducible endothelium specific Sirt3 knockout (Ec
Sirt3KO
), endothelial Sirt3 overexpressing (Ec
Sirt3OX
), smooth muscle Sirt3 knockout (Smc
Sirt3KO
), smooth muscle Sirt3 overexpressing (Smc
Sirt3OX
) and global Sirt3 overexpressing (Sirt3OX) mice on C57Bl/6J background, and examined the effect of Sirt3 expression on vascular dysfunction and angiotensin II-induced hypertension. It was found that cell-specific Sirt3 depletion in endothelial and smooth muscle in Ec
Sirt3KO
and Smc
Sirt3KO
mice increases vascular permeability by 2-fold, raises T cell and monocyte vascular accumulation, diminishes endothelial NO and increases blood pressure by 10 mm Hg compared with wild-type Sham mice. Angiotensin II infusion in Ec
Sirt3KO
and Smc
Sirt3KO
mice caused vascular hyperpermeability, increased vascular hypertrophy, exacerbated endothelial dysfunction and hypertension. Meanwhile, Sirt3 overexpression reduced vascular permeability and diminished vascular inflammation compared to Sham wild-type mice. Sirt3 overexpression in endothelial and smooth muscle prevents angiotensin II-induced vascular hyperpermeability, inhibits vascular oxidative stress, preserves endothelial-dependent relaxation, diminishes vascular hypertrophy and attenuates hypertension by 20 mm Hg in angiotensin II-infused Ec
Sirt3OX
and Smc
Sirt3OX
mice compared with the wild-type littermates. Interestingly, Sirt3 depletion in human aortic endothelial cells and human vascular smooth muscle cells reduces expression of differentiation markers. We suggest that Sirt3 is central in redox and metabolic regulations of smooth muscle and endothelial cells. Our data support a therapeutic potential of targeting Sirt3 in vascular dysfunction and hypertension.
Abstract 063: Urinary Mitochondrial DNA Copy Number Identifies Renal Mitochondrial Injury in Renovascular Hypertensive Patients Undergoing Renal Revascularization
Authors: Eirin Alfonso , Herrmann Sandra M , Saad Ahmed , Tang Hui , Lerman Amir , Lerman Lilach O
Published: December 2018

Background:
We have previously shown in patients with renovascular hypertension (RVH) that elevated urinary mtDNA copy numbers represent surrogate markers of renal mitochondrial injury. Revascularization with percutaneous transluminal renal angioplasty (PTRA) can lead to acute renal reperfusion injury. However, whether PTRA induces renal mitochondrial injury remains unknown.

Methods:
We prospectively measured urinary copy number of the mtDNA genes cytochrome-c oxidase-3 (COX3) and NADH dehydrogenase subunit-1 (ND1) by qPCR in 5 RVH patients before and 24hrs after PTRA. Five additional patients were treated before and during PTRA with the mitoprotective drug elamipretide (ELAM, 0.05 mg/kg/hr IV infusion). Healthy volunteers (HV) served as controls (n=5).

Results:
Baseline blood pressure was similarly elevated in both RVH groups, and eGFR lower than HV (Table). Baseline urinary COX3 and ND1 levels were similarly higher in both RVH groups compared with HV (Fig. A), and directly correlated with serum creatinine levels (R
2
=0.74, p=0.001 and R
2
=0.45, p=0.033, respectively). Over 3 months, eGFR increased only in ELAM-treated patients (Fig. B). Furthermore, the rise in urinary mtDNA 24hrs after PTRA was blunted in PTRA+ELAM versus PTRA+Placebo, and inversely correlated with the change in eGFR of 3 months after PTRA (Fig. C).

Conclusion:
PTRA induces an acute rise in urinary mtDNA levels, likely reflecting renal mitochondrial injury due to reperfusion injury that inhibits renal recovery. Mitoprotection in this cohort limited PTRA-associated mitochondrial injury and improved renal outcomes after revascularization.
Abstract 068: Kelch-Like 3 Dephosphorylation by Calcineurin as a Mechanism Regulating Na-cl Cotransporter
Authors: Wang Qin , Ishizawa Ken-ichi , Yamazaki Osamu , Tamura Yoshifuru , Fujigaki Yoshihide , Uchida Shunya , Shibata Shigeru
Published: December 2018

Tacrolimus, an inhibitor of the phosphatase calcineurin, is widely used as an immunosuppressive agent. However, its use is associated with hypertension and hyperkalemia. Although previous studies indicated that the activation of thiazide-sensitive, Na-Cl cotransporter (NCC) plays a key role in the pathogenesis, the identity of the direct target of calcineurin in kidney remained unclear. Kelch-like 3 (KLHL3) is a component of an E3 ubiquitin ligase that critically regulates NCC function. In pseudophyoaldoseronism type 2, the disease-causing mutations in KLHL3 impair binding and degradation of with-no-lysine 1 (WNK1) and WNK4, resulting in hypertension and hyperkalemia that are correctable by thiazide. Previously, we reported that phosphorylation of KLHL3 at serine 433 (KLHL3
S433-P
) by protein kinase C critically regulates KLHL3 function by abrogating the substrate-binding ability. However, phosphatases responsible for KLHL3
S433-P
regulation were unknown. We here show that calcineurin acts as a phosphatase for KLHL3
S433-P
. In in vitro phosphatase assay, we found that calcineurin suppressed KLHL3
S433-P
levels (65% reduction from baseline). Consistently, the activation of calcineurin by ionomycin significantly reduced KLHL3
S433-P
abundance in distal convoluted tubule cells and in HEK cells expressing KLHL3, an effect that was almost completely prevented by calcineurin knockdown. Moreover, we found that tacrolimus increased KLHL3
S433-P
levels by 1.8 fold in mouse kidney, which was associated with the WNK accumulation and increased NCC activity. Finally, we found that tacrolimus attenuated KLHL3-mediated WNK4 ubiquitination and degradation, and this effect was abolished by non-phosphorylatable S433A substitution in KLHL3. These data identify Kelch-like 3 as a direct target of calcineurin, and provide evidence that KLHL3 is involved in the pathophysiology of tacrolimus-induced hypertension.
Abstract 079: Long-Lasting RNAi Therapeutics Targeting Angiotensinogen Induces a Robust and Durable Antihypertensive Effect
Authors: Uijl Estrellita , Mirabito Colafella Katrina M , van Veghel Richard , de Vries René , Garrelds Ingrid M , Hoorn Ewout J , Poglitsch Marko , Kim Jae , Foster Don , Danser A.H. Jan
Published: December 2018

All angiotensin stems from angiotensinogen (AGT). A single dose of small interfering ribonucleic acids (siRNA) targeting AGT may provide long-lasting blood pressure reductions, as it would abolish angiotensin generation. Here we assessed efficacy of AGT siRNA in spontaneously hypertensive rats (SHRs). SHRs were treated for 4 weeks with vehicle, siRNA (10 mg/kg; s.c. every 2 weeks), valsartan (31 mg/kg/day; oral), captopril (100 mg/kg/day; oral), valsartan+siRNA, or captopril+valsartan (all groups n=8). Mean arterial pressure (MAP) was measured via radiotelemetry. Baseline MAP was 137±2 mmHg. ΔMAP was largest after valsartan+siRNA (-67±3 mmHg; P<0.01 vs. captopril+valsartan), followed by captopril+valsartan, captopril, siRNA and valsartan (-55±4, -24±2, -14±1, and -9±2 mmHg, respectively). Valsartan+siRNA reduced cardiac hypertrophy the most (P<0.05 vs. captopril+valsartan). After 4 weeks, siRNA lowered AGT by 98.6%, which increased to 99.9% in combination with valsartan. All treatments increased renin, the highest rise occurring after valsartan+siRNA. Yet, only valsartan+siRNA lowered angiotensin II. No treatment altered aldosterone. Plasma K
+
tended to increase in all groups, significance being reached only in the valsartan+siRNA group. Both types of dual blockade attenuated normal growth from the second week of treatment onwards. In conclusion, due to renin upregulation, circulating angiotensin II remained intact even with only 1.4% of AGT left, relative to pretreatment. Consequently, AGT siRNA caused a similar antihypertensive effect as valsartan and captopril. Importantly, when combining siRNA+valsartan, angiotensin II collapsed, and blood pressure decreased synergistically. Given the potential for low dosing frequency suggested by this study, this novel treatment may address medication adherence problems in patients with resistant hypertension and further development is warranted.
Abstract 084: Selective Renal Afferent Denervation Enhances Diuretic and Natriuretic Response to Glucagon-like Peptide-1 in Rats With Heart Failure
Authors: Katsurada Kenichi , Sharma Neeru M , Zheng Hong , Liu Xuefei , Patel Kaushik
Published: December 2018

Glucagon-like peptide-1 (GLP-1), incretin hormone, has diuretic and natriuretic effects and its receptor agonist reduces cardiovascular events. The present study was designed to determine whether GLP-1-induced diuresis is regulated by renal nerve in the rats with a coronary ligation model of heart failure (HF). Our immunohistochemistry and immunoblotting studies demonstrate that GLP-1 receptors were expressed in the renal pelvic wall, densely innervated by afferent renal nerves (ARN). Basal ARN activity (ARNA) was increased in HF compared to normal rats (1.3 ± 0.2* vs. 0.6 ± 0.1 μV·s). GLP-1 (3μM) infused into left renal pelvis increased ipsilateral ARNA in both normal and HF rats. The change in basal ARNA and the maximum ARNA represented as percent activation by injection of capsaicin (transient receptor potential V1 receptor agonist, 100μM) were higher in HF than in normal rats (ΔARNA 227 ± 27%* vs. 131 ± 26%, and ARNAmax 64.2 ± 3.4%* vs. 45.1 ± 6.6%). Intravenous infusion of GLP-1 (1μg/kg/min) for 30 min increased renal urine flow and sodium excretion in normal rats and these effects were blunted in HF (Urine flow 1577 ± 122* vs. 1981 ± 101 μl/gkw, Sodium excretion 221 ± 19* vs. 284 ± 15 μEq/gkw). GLP-1-induced diuresis and natriuresis were enhanced by total renal denervation (T-RDN) with acute surgical cutting of the renal nerves in both normal and HF rats. The degree of diuretic and natriuretic responses to GLP-1 were greater in HF than in normal rats (increased % rate: Urine flow 167%* vs. 135%, Sodium excretion 169%* vs. 150%). Selective afferent renal denervation (A-RDN) was performed by bilateral perivascular application of capsaicin (33mM) on the renal nerves. Ten days after A-RDN, there was an enhanced diuretic and natriuretic response to GLP-1 in both normal and HF rats. These effects were greater in HF than in normal rats (increased % rate: Urine flow 187%* vs. 130%, Sodium excretion 147%* vs. 138%). Urine flow and sodium excretion responses to GLP-1 were not significantly different between T-RDN and A-RDN in both groups. Taken together our results indicate that the diuretic and natriuretic effects of GLP-1 are partly governed via ARN activation. GLP-1-induced diuresis and natriuresis enhanced by RDN have potential therapeutic implication for HF.
Abstract 089: Deletion of Circadian Clock Associated Gene,
Rfwd2
, Alters Rhythm in Blood Pressure Timing Without Changes in Salt-Sensitivity
Authors: Chen Daian , Booth John N , Becker Bryan K , Colson Jackson C , Jin Chunhua , Cowley Allen W , Geurts Aron , Muntner Paul , Young Martin E , Pollock David M , Pollock Jennifer S
Published: December 2018

Healthy individuals display a diurnal blood pressure (BP) rhythm and salt-sensitivity increases the susceptibility for dysfunctional BP rhythms. Previously, bayesian modeling found that
Rfwd2
gene was associated with circadian clock gene pathways in the Dahl Salt-sensitive rats (SS). SS rats lacking
Rfwd2
were generated to test the hypothesis that
Rfwd2
alters the circadian BP rhythm and salt-sensitivity in SS rats.
Rfwd2
total knockout rats on the SS background are embryonic lethal, thus experiments utilized male
Rfwd2
heterozygous SS (

Rfwd2
+/-
;

n=6) and SS rats (n=8). All rats were maintained on Teklad (NIH-31) normal salt diet (NS; 0.4% NaCl) and then fed high salt diet (HS; 4% NaCl). BP was recorded via telemetry and systolic BP analyzed on days 4-7 of diet. On NS, the amplitude (difference between peak and mean) and mesor (rhythm-adjusted mean) were similar between genotypes. However, HS diet increased the amplitude (SS: 5.2 ± 0.4 to 9.3 ± 0.5, P<0.0001; Rfwd2
+/-
: 3.7 ± 0.5 to 9.0 ± 0.5, P<0.0001) and mesor (SS: 147 ± 1.2 mmHg to 166 ± 1.7 mmHg, P<0.0001; Rfwd2
+/-
: 150 ± 1.6 mmHg to 177 ± 3.1 mmHg, P<0.0001) in both genotypes. On HS, Rfwd2
+/-
rats compared to SS had greater mesor (178 ± 3.1 mmHg vs. 166 ± 1.7 mmHg, P=0.003, respectively) and similar amplitude. Rfwd2
+/-
had significant 1.4hr delay in trough (lowest value) SBP timing compared to SS within both salt diets (NS: P=0.005; HS: P=0.008). In addition, HS caused a delay in trough SBP timing in both genotypes. These results (figure) show that
Rfwd2
has a role in trough BP timing, and the lack of this gene results in an exaggerated mesor on HS diet and a 1.4hr delay on NS and HS diets, which could potentially be coupled with renal injury.
Abstract 102: G-Protein Coupled Protein Kinase 4 Variants Differentially Modulate Response of Breast Cancer Cells to Dopamine 1 Receptor Agonist
Authors: Yue Wei , Tran Hanh , Wang Jiping , Schiermeyer Katherine A , Xu Peng , Gildea John J , Felder Robin A
Published: December 2018

Breast cancer incidence is higher in hypertensive women yet no biochemical basis has been reported for this link. Dopaminergic D1-like receptor (D
1
R) regulates renal sodium excretion and blood pressure. Uncoupling of D
1
R from its G protein/effector enzyme complex resulted from constitutive activation of GRK4 impairs the regulation and leads to hypertension. Our prior studies have shown the essential role of GRK4 gene variants in hypertension. Elevated expression of D
1
R is associated with aggressive breast cancer. On the other hand, GRK4 expression is also reported higher in breast cancer than in normal breast tissues. The current study tested our hypothesis that GRK4 variants differentially affect breast cancer cell viability. We first used MCF-7 breast cancer cells as a model to determine the effect of GRK4 expression on baseline growth. To avoid interference of endogenous GRK4, we used shRNA to knockdown cMyc, the transcription factor that regulates GRK4 and expressed GRK4α, GRK4γ, and GRK4γ with 3 SNPs, R65L, A142V, A486V (GRK4γ TM). cMyc KD significantly reduced the growth rate of MCF-7 cells (doubling time is 3-fold longer than the wild type cells). Expression of 3 isoforms of GRK4 offset the growth retardation of cMyc KD. The effect of GRK4γ was weaker than that of GRK4α and GRK4γ TM. Interestingly, while all offered a growth advantage the cells with different GRK4 subtypes showed different responses to the D
1
R agonist SKF38393. Wild type and GRK4γ expressing MCF-7 were resistant to SKF with less than 30% inhibition (286545/364447, 67909/91592) at 40 μM. In contrast, GRK4α and GRK4γ TM expressing cells were inhibited by more than 80% (9878/72721, 19228/118371) at the same concentrations. To confirm the role of GRK4, we chose 3 breast cancer cell lines that naturally express GRK4 with 0, 1, and 2 SNPs and compared their responses to SKF38393. Similar to the MCF-7 expressing GRK4α and GRK4γ TM, MDA-MB-468 cells containing 2 SNPs were more sensitive to SKF38393 with 98% inhibition (24937/1143137). BT-20 cells which have no SNP showed the least growth inhibition (29%, 96245/353854). While unexpected and with unknown mechanism, our data implicate a new therapeutic potential for use of a D
1
R agonist for breast cancer treatment with aberrant expression of GRK4.
Abstract 112: Carotid Artery Stiffness Increases the Risk of Incident Depressive Symptoms: The Paris Prospective Study 3
Authors: van Sloten Thomas T , Boutouyrie Pierre , Tafflet Muriel , Thomas Frédérique , Guibout Catherine , Climie Rachel E , Lemogne Cédric , Pannier Bruno , Laurent Stéphane , Jouven Xavier , Empana Jean-Philippe
Published: December 2018

Introduction:
Late-life depression is related to poor quality of life, functional impairment, and increased risk of mortality and cardiovascular disease. Effective interventions for prevention and treatment of late-life depression need to be developed, which requires a better understanding of late-life depression risk factors. Arterial stiffness, an important cardiovascular disease risk factor, may contribute to late-life depression via cerebrovascular damage, but evidence is scarce.

Aim:
We investigated the association between carotid artery stiffness and incident depressive symptoms in a large community-based cohort study.

Methods:
This longitudinal study included 7,013 participants (60 (SD 6) years; 36% women) free of depressive symptoms at baseline. Carotid stiffness (high-resolution echotracking) was determined at baseline. Presence of depressive symptoms was determined at baseline and at 4 and 6 years of follow-up, and was defined as a score ≥7 on a validated 13-item questionnaire (Q2DA) and/or new use of antidepressants. Cox regression and generalized estimating equations (GEE) were used.

Results:
In total, 6.9% (n=484) of the participants had incident depressive symptoms at 4 or 6 years of follow-up. Greater carotid stiffness was associated with a higher incidence of depressive symptoms (Figure). Results were qualitatively similar when GEE was used instead of Cox regression.

Conclusions:
Greater carotid stiffness is associated with a higher incidence of depressive symptoms. This study supports the hypothesis that carotid stiffness contributes to the development of late-life depression.