Vascular Hypertrophy Research Articles

15‐LO/15‐HETE Mediated Vascular Adventitia Fibrosis via p38 MAPK‐Dependent TGF‐β

15-Lipoxygenase/15-hydroxyeicosatetraenoic acid (15-LO/15-HETE) is known to modulate pulmonary vascular medial hypertrophy and intimal endothelial cells migration and angiogenesis after hypoxia. However, it is unclear whether 15-HETE affects the adventitia of the pulmonary arterial wall. We performed immunohistochemistry, adventitia fibrosis, pulmonary artery fibroblasts phenotype and extracellular matrix (ECM) deposition to determine the role of 15-HETE in hypoxia-induced pulmonary vascular adventitia remodeling. Our studies showed that O2 deprivation induced adventitia hypertrophy of pulmonary arteries with ECM accumulation in both humans with pulmonary arterial hypertension and hypoxic rats. Hypoxia induced 15-LO expression in adventitia. With the inhibitor, NDGA depressed the hypoxia induced ECM deposition and 15-LO production in hypoxic rats. Hypoxia up-regulated the expression of α-SMA, type-Ia collagen and fibronectin in cultured fibroblasts, which seemed to be due to the increased 15-LO/15-HETE. Exogenous 15-HETE mediated the ECM and phenotypic alterations of the fibroblasts as well. The 15-LO/15-HETE induced adventitia fibrosis and fibroblasts phenotypic alterations depended on signaling of the transforming growth factor-β1 (TGF-β1)/Smad2/3 pathway. P38 mitogen-activated protein kinase (p38 MAPKs) was likely to mediate 15-LO induced TGF-β1 and Smad2/3 activation after hypoxia. The results suggest that adventitia fibrosis is an important event in the hypoxia induced pulmonary arterial remodeling, which relies on 15-LO/15-HETE induced p38 MAPK-dependent TGF-β1/Smad2/3 intracellular signaling systems.

Effects of the dual TP receptor antagonist and thromboxane synthase inhibitor EV-077 on human endothelial and vascular smooth muscle cells

The prothrombotic mediator thromboxane A2 is derived from arachidonic acid metabolism through the cyclooxygenase and thromboxane synthase pathways, and transduces its effect through the thromboxane prostanoid (TP) receptor. The aim of this study was to determine the effect of the TP receptor antagonist and thromboxane synthase inhibitor EV-077 on inflammatory markers in human umbilical vein endothelial cells and on human coronary artery smooth muscle cell proliferation. To this end, mRNA levels of different proinflammatory mediators were studied by real time quantitative PCR, supernatants were analyzed by enzyme immune assay, and cell proliferation was assessed using WST-1. EV-077 significantly decreased mRNA levels of ICAM-1 and PTX3 after TNFα incubation, whereas concentrations of 6-keto PGF1α in supernatants of endothelial cells incubated with TNFα were significantly increased after EV-077 treatment. Although U46619 did not alter coronary artery smooth muscle cell proliferation, this thromboxane mimetic enhanced the proliferation induced by serum, insulin and growth factors, which was significantly inhibited by EV-077. In conclusion, EV-077 inhibited TNFα-induced endothelial inflammation and reduced the enhancement of smooth muscle cell proliferation induced by a thromboxane mimetic, supporting that the thromboxane pathway may be associated with early atherosclerosis in terms of endothelial dysfunction and vascular hypertrophy.

Antioxidant effect of doxycycline decreases MMP activity and blood pressure in SHR

Increased matrix metalloproteinase (MMP) levels are involved in vascular remodeling of hypertension. In this study, we hypothesized that doxycycline (a MMP inhibitor) could exert antioxidant effects, reverse establish vascular remodeling, and lower blood pressure in spontaneously hypertensive rats (SHR). SHR and Wistar-Kyoto rats received either doxycycline at 30mg/kg/day by gavage or vehicle. Systolic blood pressure (SBP) was assessed weekly by tail cuff. After 5weeks of treatment, morphologic changes in the aortic wall were studied in hematoxylin/eosin sections. MMP activity and expression were determined by in situ zymography using DQ gelatin and immunofluorescence for MMP-2. Dihydroethidium was used to evaluate aortic reactive oxygen species (ROS) production by fluorescence microscopy. Doxycycline reduced SBP by 25mmHg. However, the antihypertensive effects were not associated with significant reversal of hypertension-induced vascular hypertrophy. SHR showed increased aortic MMP-2 levels which co-localized with higher aortic MMP activity and ROS levels, and all those biochemical alterations associated with hypertension were blunted by treatment with doxycycline. These results show that MMP inhibition with doxycycline in SHR with established hypertension resulted in antioxidant effects, lower gelatinolytic activity, and antihypertensive effects which were not associated with reversal of hypertension-induced vascular remodeling.

Abstract 610: Cardiac and Vascular Hypertrophy Produced by Angiotensin II is Associated with Increases of mTOR/P70S6 Kinases Expression

It is fairly well-accepted now that Angiotensin II (Ang II)-infusion produces hypertension and cardiac as well as vascular hypertrophy. In cell culture, the mammalian target of rapamycin (mTOR) and its effector kinase (P70S6) have been shown to increase in cardiomyocytes and smooth muscle cells in response to Ang II and have been suggested to contribute to hypertrophy in these two cell types. The goal of this study was to test the Ang II infusion is associated with increased mTOR and P70S6 expression in vivo . C57BL/6 mice (3 mo of age) were subjected to either sham (control) surgery or surgically implanted with osmotic containing Ang II (1000ng/mit/kg). In mice implanted with Ang II, systolic blood pressure (SBP) was 134±10 mmHg versus 120±5 in control mice. The heart hypertrophy was indicated by heart weight in Ang II group with 30% heavier than the sham controls (mean ± SEM 165.1 ± 5.5 mg versus 126.4 ± 2.9 mg, P<0.01). Quantitative densitometry evaluation of Western Blot showed the ratio 2447 phosphorylated mTOR / total mTOR was significantly elevated in the heart of AngII group with 54% greater than controls (0.51 ± 0.06 versus 0.33 ± 0.01, P < 0.05); and p389-P70S6/total P70S6 was increased by ~75% in Ang II group versus controls (0.07 ± 0.009 to 0.04 ± 0.002 in Ang II-infused and sham mice, respectively, P<0.05). Similarly, p-mTOR/t-mTOR expression increased by ~17% with Ang II treatment (e.g., p-mTOR/t-mTOR expression was 0.69 ± 0.14 to 0.59 ± 0.14 in Ang II-infused and sham mice, respectively, P<0.05); and p-P70S6 / t-P70S6 in Ang II - infused mice was over 50% greater than controls (0.73 ± 0.15 versus 0.46 ± 0.14, P=0.055). Conclusion: mTOR/P70S6 upregulation in the aorta and the heart induced by AngII stimulation indeed happened in vivo and indicates mTOR/P70S6 may play important roles in cardiovascular hypertrophy. Also, they may serve as biomarkers or therapeutics indications. The mechanism of mTOR/P70S6 signaling pathway causing hypertrophy should be further explored.

Right Ventricular Electrical Remodeling and Arrhythmogenic Substrate in Rat Pulmonary Hypertension

Right ventricular (RV) dysfunction, caused by severe pulmonary hypertension (PH), is associated with high mortality because of RV failure. However, some patients can suffer from sudden cardiac death (SCD). We hypothesized that severe PH can cause RV arrhythmogenesis, leading to SCD. We sought to investigate arrhythmogenesis in PH. Optical mapping analysis (OMP) with an electrophysiological study (EPS) and pathological examination were performed in a monocrotaline (MCT)-induced rat PH model. Rats were injected with MCT (60 mg/kg), and OMP was performed in isolated Langendorff-perfused hearts. OMP revealed abnormal RV conduction delays and abnormal patterns, along with elevated RV pressure. In addition, impaired action potential duration dispersion (APDd), an index of myocardial repolarization instability, was observed only in the RVs with severe PH. The EPS demonstrated that lethal arrhythmias were induced by burst pacing to the RV when deteriorated APDd became evident. This arrhythmogenesis was inhibited by combination treatment with sildenafil and beraprost (SIL + BERA). RT-PCR showed an mRNA up-regulation of Type I collagen and down-regulation of connexin-43 in the RV at 5 weeks after MCT injection. Pathological examination revealed pulmonary vascular remodeling and RV hypertrophy with interstitial fibrosis, which was substantially reduced by SIL + BERA. Immunohistochemistry also revealed connexin-43 degradation in the RVs with severe PH. In contrast, connexin-43 was well preserved, and no lethal arrhythmias were induced by burst pacing to the RV in the absence of PH after SIL + BERA. In conclusion, RV electrical remodeling, including impaired APDd, causes arrhythmogenesis in severe PH, potentially associated with SCD attributable to PH.

Abstract 202: Activation of Cyp4a12-20-HETE Synthase Increases Blood Pressure and Promotes Vascular Hypertrophy and Cardiac Dysfunction

20-Hydroxyeicosatetraenoic acid (20-HETE) is a microcirculatory cytochrome P450-derived eicosanoid shown to increase smooth muscle contractions and proliferation, stimulate endothelial dysfunction and activation, and promotes hypertension. We developed a mouse model (Cyp4a12tg) in which the expression of Cyp4a12, the sole 20-HETE synthase in mouse, is under the control of the doxycycline (DOX) promoter. Administration of DOX to Cyp4a12tg mice increased blood pressure (131±3 vs 100±2 mmHg, p<0.05), which was prevented by co-treatment with the 20-HETE antagonist, 20-HEDGE (96±3 mmHg, p<0.05). Media-to-lumen ratio and medial cross sectional area of renal microvessels from DOX-treated Cyp4a12tg mice significantly increased compared to untreated (M/L, 0.15±0.01 vs 0.07±0.01; mCSAx103 10.8±0.92 vs. 6.4±0.48 mm2); these increases were abolished by co-treatment with 20-HEDGE. Cardiac output and heart rate were unchanged, whereas %EF and %FS were reduced and LV volume and diameter at systole increased in DOX-treated Cyp4a12tg. Total peripheral resistance (TPR) was significantly increased in DOX-treated Cyp4a12tg mice (8.00±0.39 vs 6.77±0.36 mmHg/ml/min, p<0.05); co-treatment with 20-HEDGE decreased (p<0.0%) DOX-induced TPR in Cyp4a12tg mice (7.45±0.22 mmHg/ml/min). These results indicate that activation of Cyp4a12-20-HETE synthase causes hypertension, microvascular remodeling, and cardiac dysfunction. The results also suggest that 20-HETE promotes hypertension by increasing TPR. However, the mechanisms underlying Cyp4a12-20-HETE-driven microvascular remodeling and cardiac dysfunction are yet to be explored.

Abstract 645: Atorvastatin and Sildenafil Reduce Oxidative Stress, MMP-2 And MMP-9 Levels, TGF-beta Expression and Prevent Vascular Remodeling in 2K1C-hypertension

Hypertension-induced vascular remodeling is associated with oxidative stress, and matrix metalloproteinase (MMP) and TGF (transforming growth factor)-beta up-regulation. Atorvastatin (ATORVA) and sildenafil (SILD) exert pleiotropic effects that may result in cardiovascular protection. We evaluated the effects of ATORVA and SILD alone or in association on oxidative stress, MMPs and TGF-beta up-regulation, and vascular hypertrophy induced by 2 kidney-1 clip (2K1C) hypertension. Sham and 2K1C rats were orally treated with vehicle, ATORVA (50 mg/kg), SILD (45 mg/kg) or both for 8 weeks. ATORVA, SILD, or both drugs exerted antihypertensive effects (systolic blood pressure: 148±7, 156±5, and 138±4 mmHg, respectively, vs. 207±4 mmHg in 2K1C untreated rats; P<0.05). All treatments prevented the increases in the aortic cross-sectional area and media/lumen ratio in 2K1C rats (P<0.05). Hypertension increased NADPH oxidase activity when compared with control groups and the treatments reduced oxidative stress. Aortas from 2K1C rats showed higher MMP-2 levels when compared with sham (0.399±0.06 vs. 0.173±0.05 A.U.) and all treatments attenuated 2K1C hypertension-induced increases in MMP-2 levels (ATORVA: 0.191±0.04; SILD: 0.136±0.05; ATORVA+SILD: 0.173±0.03; P<0.05). However, these drugs had no in vitro effects on human recombinant MMP-2 activity (P>0.05). Moreover, 2K1C rats showed higher MMP-9 (12.64±0.86 vs. 8.70±0.92) and TGF-beta expression (14.25±0.97 vs. 9.07±1.67) compared with sham groups. All treatments prevented 2K1C hypertension-induced increases in these pro-fibrotic factors. Treatment with ATORVA or SILD, or both, exerted antihypertensive effects and prevented 2K1C hypertension-induced vascular remodeling through antioxidant and anti-fibrotic mechanisms. Our results suggest that ATORVA and SILD may prevent the vascular alterations of hypertension.

Renin-angiotensin-aldosterone system gene variants and their association with left ventricular function and vascular properties in essential hypertension

Purpose: The role of the renin-angiotensin-aldosterone system in the pathophysiology of organ damage still remains elusive. The angiotensinogen M235T and aldosterone synthase C-344T gene polymorphisms may be associated with vascular indices, renal function and left ventricular hypertrophy. Therefore, in the present study we sought to investigate their potential associations with left ventricular function and vascular properties in essential hypertension. Methods: The study population consisted of 319 untreated patients, newly diagnosed stage I–II essential hypertension and a control group, consisted of 191 age-matched for classical cardiovascular risk factors. The gene mutations frequencies was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. In all participants, flow mediated dilation (FMD), pulse wave velocity (PWV), intima-media thickness (IMT), as well as the incidence and progression of retinopathy were evaluated. Left cardiac indices were assessed by echocardiography. Glomerular filtration rate (GFR) was estimated by Cockcroft-Gault formula. Results: 235TT homozygotes compared with M-carriers had significantly lower FMD in controls (p=0.038) and higher PWV values in hypertensive patients (p=0.025). Regarding other vascular properties no other significant associations were observed. TT homozygosity showed a trend towards lower GFR compared with MM+MT genotype in hypertensive patients (99.9±30.2 vs 106.8±35.3 mL/min/1.73 m2, p=0.067) but neither genotype was associated with increased creatinine. Notably, we observed higher values of IMT in -344TT homozygosity, in the group of hypertensives (781.6±33.5 vs 712.5±16.2 μm, p=0.039). Moreover, -344TT hypertensives exhibited higher values of left ventricular mass index compared to C-allele carriers (p=0.020) and higher prevalence of concentric hypertrophy (p<0.001). Conclusions: The present study suggests that aldosterone synthase is associated with left ventricular hypertrophy, while angiotensinogen is associated with endothelial dysfunction, increased IMT and arterial stiffness in untreated hypertension. These findings suggest that both variants play important role in the pathophysiology of hypertension.

Regression of target organ damage

Regression of target organ damage

New dicoumarol sodium compound: crystal structure, theoretical study and tumoricidal activity against osteoblast cancer cells

BackgroundEnormous interest had been paid to the coordination chemistry of alkali and alkaline metal ions because of their role inside body viz; their Li+/Na+ exchange inside the cell lead to different diseases like neuropathy, hypertension, microalbuminuria, cardiac and vascular hypertrophy, obesity, and insulin resistance. It has been presumed that alkali metal ions (whether Na+ or K+) coordinated to chelating ligands can cross the hydrophobic cell membrane easily and can function effectively for depolarizing the ion difference. This unique function was utilized for bacterial cell death in which K+ has been found coordinated valinomycin (antibiotic).ResultsDistinct sodium adduct (1) with dicoumarol ligand, 4-Hydroxy-3-[(4-hydroxy-2-oxo-4a,8a-dihydro-2H-chromen-3-yl)-phenyl-methyl]-chromen-2-one (L) is isolated from the saturated solution of sodium methoxide. Single crystal X-ray diffraction studies of the adduct reveals that sodium is in the form of cation attached to a methoxide, methanol and a dicoumarol ligand where carbonyl functional groups of the coumarin derivative are acting as bridges. The sodium compound (1) is also characterized by IR, 1H-NMR, and 13C{1H}-NMR spectroscopic techniques. The composition is confirmed by elemental analysis. DFT study for 1 has been carried out using B3LYP/6-13G calculations which shown the theoretical confirmation of the various bond lengths and bond angles. Both the compounds were studied subsequently for the U2OS tumoricidal activity and it was found that L has LD50 value of 200 μM whereas the sodium analog cytotoxicity did not drop down below 60%.ConclusionA sodium analogue (1) with medicinally important dicoumarol ligand (L) has been reported. The crystal structure and DFT study confirm the formation of cationic sodium compound with dicoumarol. The ligand was found more active than the sodium analog attributed to the instability of 1 in solution state. Coumarin compound with sodium was observed to be less cytotoxic than the ligand, its LD50 value never dropped below 60%.

Digital gene expression analysis of corky split vein caused by boron deficiency in 'Newhall' Navel Orange (Citrus sinensis Osbeck) for selecting differentially expressed genes related to vascular hypertrophy.

Corky split vein caused by boron (B) deficiency in ‘Newhall’ Navel Orange was studied in the present research. The boron-deficient citrus exhibited a symptom of corky split vein in mature leaves. Morphologic and anatomical surveys at four representative phases of corky split veins showed that the symptom was the result of vascular hypertrophy. Digital gene expression (DGE) analysis was performed based on the Illumina HiSeq™ 2000 platform, which was applied to analyze the gene expression profilings of corky split veins at four morphologic phases. Over 5.3 million clean reads per library were successfully mapped to the reference database and more than 22897 mapped genes per library were simultaneously obtained. Analysis of the differentially expressed genes (DEGs) revealed that the expressions of genes associated with cytokinin signal transduction, cell division, vascular development, lignin biosynthesis and photosynthesis in corky split veins were all affected. The expressions of WOL and ARR12 involved in the cytokinin signal transduction pathway were up-regulated at 1st phase of corky split vein development. Furthermore, the expressions of some cell cycle genes, CYCs and CDKB, and vascular development genes, WOX4 and VND7, were up-regulated at the following 2nd and 3rd phases. These findings indicated that the cytokinin signal transduction pathway may play a role in initiating symptom observed in our study.

Sinusoidal Constriction and Vascular Hypertrophy in the Diabetes-Induced Rabbit Penis

To assess the morphological changes of penile vascular structures and the corpus cavernosum area in alloxan-induced diabetic rabbits. Twenty male rabbits (2 months old) were divided into two groups with 10 rabbits each, the control group (CG) and the diabetic group (DG). The animals from DG received an intravenous injection of alloxan (100mg/kg) to induce the diabetes. Ten weeks after the induction of diabetes, all animals were euthanized. Two fragments of the penile shaft were harvested and samples were processed and paraffin embedded. Sections (5 µm) were cut and stained for histological and immunohistochemical markers. Nuclear protrusion toward the lumen, and cytoplasmic vacuolization were observed in the tunica intima of the dorsal artery of the penis in DG. The thicknesses of the tunica media increased significantly in DG (p = 0.0350). It was also observed a significant increase in the area of the tunica media (p = 0.0179). There was no significant change in smooth muscle cell density in the tunica media of the dorsal artery of the penis (p = 0.0855). The collagen fiber pattern of the tunica adventitia of the dorsal artery of the penis was different between the control and diabetic groups. There was a significant decrease in the area occupied by the cavernous sinuses in DG (p = 0.0013). Alloxan-induced diabetes mellitus in rabbits promotes important changes in penile vascular structures, thereby decreasing blood supply and affecting penile hemodynamics, leading to erectile dysfunction.

THU0347 Central Blood Pressure in Patients with Ankylosing Spondylitis

BackgroundCentral (aortic) blood pressure (BP), which is the pressure exerted on the heart and brain, may be different from the pressure that is measured at the arm. Clinical studies have...

Esmolol treatment reduces plasmatic oxidative stress and vascular hypertrophy in spontaneously hypertensive rats

Esmolol treatment reduces plasmatic oxidative stress and vascular hypertrophy in spontaneously hypertensive rats

Endothelial Dysfunction in Diabetes – Clasic Sources of Vascular Oxidative Stress (Nadph Oxidases, Enos Uncoupling and Xanthine Oxidase)

Abstract Cardiovascular disease is the leading cause of disease / mortality worldwide. It is generally accepted that increased production of reactive oxygen species (ROS) has an important role in cardiovascular pathology, contributing to endothelial dysfunction and to the aggravation of atherosclerosis. Among all cardiovascular risk factors, diabetes mellitus is one of the most important. The worldwide prevalence of diabetes has increased rapidly even in developing countries, doubling the combined risk of cardiovascular events in patients with hypertension. In diabetes, increased reactive oxygen species (ROS) production leads to endothelial dysfunction, recognized by the presence of impaired vascular relaxation, increased vascular smooth muscle cells growth and hypertrophy, all together contributing to atherosclerotic plaque formation. On this basis, the vascular endothelium has emerged as a therapeutic target, with the aim to improve systemic metabolic state by improving vascular function. In this review we have focused on the most important sources of reactive oxygen species generated by vascular endothelium in diabetic patients (NADPH Oxidases, eNOS uncoupling, Xanthine oxidase). The importance of oxidative stress in mediating the vascular complications of diabetes is supported by studies showing that antioxidant therapy correct the vascular function in humans or in experimental models of diabetes. Therefore, understanding the physiological mechanisms involved in vascular disorders resulting from hyperglycemia is essential for the proper use of available therapeutic resources.

204 ALPHA CALCITONIN GENE-RELATED PEPTIDE PLAYS A PROTECTIVE ROLE IN BOTH AN ACUTE AND SUSTAINED MODEL OF HYPERTENSION, A MECHANISM WHICH MAY BE LINKED TO THE LOSS OF ENDOTHELIAL NITRIC OXIDE SYNTHASE (ENOS) AS THE HYPERTENSION PROGRESSES

Calcitonin gene-related peptide (CGRP) is a sensory nerve-derived neuropeptide, and its potent microvascular vasodilator activities have been suggested to be protective in a range of murine models of hypertension using...

In Vitro Assessment of Clevidipine Using the Profilin1 Hypertensive Mouse Model

Hypertension represents a major risk factor for cardiovascular events, associating with vascular hypertrophy and dysfunction in resistance vessels. Clevidipine is a novel antihypertensive drug working as a selective calcium channel antagonist with an ultra-short half-life that lowers arterial blood pressure by reducing systemic arterial resistance. The aim was to assess the effect of clevidipine on the hypertrophic vessels of profilin1 hypertensive transgenic mice compared to sodium nitroprusside (SNP) and labetalol using wire myograph techniques. The effects of clevidipine, SNP and labetalol on the hypertrophic vessels were studied on mesenteric arterial function from 8 profilin1 hypertrophic mice and eight non-transgenic controls. Our results showed a significant difference between the effects of the three drugs on the hypertrophic mesenteric arteries of transgenic profilin1 mice compared to the non-transgenic controls. The half maximal effective concentration (EC50) of clevidipine, SNP and labetalol in profilin1 mice (1.90 ± 0.05, 0.97 ± 0.07, 2.80 ± 0.05 nM, respectively) were significantly higher than the EC50 in non-transgenic controls (0.91 ± 0.06, 0.32 ± 0.06, 0.80 ± 0.09 nM, respectively). Moreover, the increase in the EC50 for clevidipine (2-fold) to produce the same effect on both normal and hypertrophic arteries was less than that of SNP (3-fold) and labetalol (3.5-fold). Therefore, we concluded clevidipine exhibited the lowest dose shift to relax the hypertrophic vessels compared to SNP and labetalol in the profilin1 hypertrophic animal mouse model.

Antioxidant-based therapies for angiotensin II-associated cardiovascular diseases

Cardiovascular diseases, including hypertension and heart failure, are associated with activation of the renin-angiotensin system (RAS) and increased circulating and tissue levels of ANG II, a primary effector peptide of the RAS. Through its actions on various cell types and organ systems, ANG II contributes to the pathogenesis of cardiovascular diseases by inducing cardiac and vascular hypertrophy, vasoconstriction, sodium and water reabsorption in kidneys, sympathoexcitation, and activation of the immune system. Cardiovascular research over the past 15-20 years has clearly implicated an important role for elevated levels of reactive oxygen species (ROS) in mediating these pathophysiological actions of ANG II. As such, the use of antioxidants, to reduce the elevated levels of ROS, as potential therapies for various ANG II-associated cardiovascular diseases has been intensely investigated. Although some antioxidant-based therapies have shown therapeutic impact in animal models of cardiovascular disease and in human patients, others have failed. In this review, we discuss the benefits and limitations of recent strategies, including gene therapy, dietary sources, low-molecular-weight free radical scavengers, polyethylene glycol conjugation, and nanomedicine-based technologies, which are designed to deliver antioxidants for the improved treatment of cardiovascular diseases. Although much work has been completed, additional research focusing on developing specific antioxidant molecules or proteins and identifying the ideal in vivo delivery system for such antioxidants is necessary before the use of antioxidant-based therapies for cardiovascular diseases become a clinical reality.

Endothelial GATA6 deficiency promotes pulmonary arterial hypertension (PAH) through ER stress‐mediated CHOP upregulation

PAH is characterized by pulmonary vasculopathy, pulmonary artery pressure and RV failure. Previous studies have implicated endoplasmic reticulum (ER) stress in several disorders, including atherosclerosis, but its involvement in PAH has not yet been investigated. GATA6 is expressed in quiescent vasculature, but is lost in vascular injury. Our goal was to investigate the role of endothelial GATA6 in mediating ER stress in PAH.Gata6 flox/flox mice were bred with mice expressing Cre under the ECs‐specific VE‐cad promoter (Gata6 CKO).Gata6 CKO mice developed PAH and had severe changes in hemodynamics under hypoxia. Furthermore, loss of GATA6 resulted in worsened vascular remodeling and RV hypertrophy in hypoxia. The ER stress‐related markers BiP, PERK, ATF4 and XBP were moderately upregulated, whereas pro‐apoptotic marker CHOP was significantly upregulated in Gata6CKO mice. Furthermore, upregulation of BiP protein was observed in Gata6CKO lungs by immunohistochemistry. Consistent with in vivo observations, depletion of GATA6 in HPAECs via siRNA resulted in upregulation of ER stress mediators including BiP, ATF4 and CHOP.Our findings suggest that GATA6 deficiency in endothelial cells leads to development of PAH, in part via upregulation of ER stress/CHOP pathway.This study was supported by NIH grant RO1 AR42334 and Postdoctoral Fellowships NIH training grant T32 AR 050958.

Epidermal Growth Factor Receptor Inhibitor PKI-166 Governs Cardiovascular Protection without Beneficial Effects on the Kidney in Hypertensive 5/6 Nephrectomized Rats

Transactivation of epidermal growth factor receptor (EGFR) signaling by G protein-coupled receptors has been implicated in several cardiovascular (CV) conditions, including hypertension, heart failure, and cardiac and vascular hypertrophy. However, the therapeutic potential of EGFR inhibition in these conditions is currently unknown. The main objective of the present study was to investigate cardiac, vascular, and renal effects of EGFR inhibition by 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol (PKI-166) in the hypertensive chronic kidney disease model. Rats underwent 5/6 nephrectomy (5/6Nx) and were treated with PKI-166, lisinopril or vehicle from week 6 after disease induction until week 12. Sham animals received either PKI-166 or vehicle. Treatment with PKI-166 did not affect the development of the characteristic renal features in 5/6Nx, including proteinuria, diminished creatinine clearance, and increased glomerulosclerosis, whereas these were attenuated by lisinopril. Despite absence of effects on progressive renal damage, PKI-166 attenuated the progression of hypertension and maintained cardiac function (left ventricle end-diastolic pressure) to a similar extent as lisinopril. Also, PKI-166 attenuated the increase in phosphorylated EGFR in the heart as induced by 5/6Nx. Moreover, PKI-166 and lisinopril restored the impaired contraction of isolated thoracic aortic rings to phenylephrine and angiotensin II and impaired myogenic constriction of small mesenteric arteries in 5/6Nx rats. Blockade of the EGFR displays a CV benefit independent of limiting the progression of renal injury. Our findings extend the evidence on EGFR signaling as a target in CV disorders.