Abstract 112: The 20-HETE Receptor: a New Player in Hypertension

Here, we report that GPR75, a G protein-coupled receptor of the Gq rhodopsin subfamily, selectively binds 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P450-derived bioactive arachidonic acid metabolite implicated in the pathogenesis of hypertension and cardiovascular diseases. In endothelial cells, 20-HETE binding to GPR75 stimulates β-arrestin recruitment and GIT1-GPR75 association, which further facilitates a c-Src-mediated transactivation of EGFR. This results in downstream signaling pathways which induce ACE expression and decrease NO bioavailability. Knockdown of GPR75 prevents 20-HETE-mediated downstream effects in endothelial cells including EGFR activation and ACE induction. In vascular smooth muscle cells, GPR75-20-HETE pairing is associated with Gα q/11 -and GIT1-mediated PKC-stimulated phosphorylation of MaxiKβ, linking GPR75 activation to 20-HETE-mediated vasoconstriction. We used the conditional Cyp4a12tg mice, which display doxycycline (DOX)-mediated hypertension along with vascular dysfunction and remodeling in a 20-HETE-dependent manner, to assess whether GPR75 is a necessary component of 20-HETE pro-hypertensive actions. Administration of GPR75-targeted shRNA lentiviral particles to DOX-treated Cyp4a12tg mice, which resulted in 80% knockdown of GPR75 knockdown, prevented blood pressure elevation (100±3 vs 135±2 mmHg) and 20-HETE-mediated increases in ACE expression, endothelial dysfunction, smooth muscle contractility and vascular remodeling when compared to DOX-treated Cyp4a12tg mice receiving non-targeted shRNA. The discovery of 20-HETE-GPR75 pairing provides the molecular basis for the signaling and pathophysiological bioactions mediated by 20-HETE in hypertension. These results clearly place GPR75 as a novel target in the control of blood pressure and vascular function.

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Abstract 310: Deoxycorticosterone Acetate (doca)-salt Exacerbates Hypertension and Vascular Dysfunction in Mice Expressing Dominant Negative Peroxisome Proliferator-activated Receptor-gamma (pparg) in Smooth Muscle

Hypertension ◽

10.1161/hyp.62.suppl_1.a310 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Pimonrat Ketsawatsomkron ◽

Deborah R Davis ◽

Aline M Hilzendeger ◽

Justin L Grobe ◽

Curt D Sigmund

Keyword(s):

Blood Pressure ◽

Smooth Muscle ◽

Transgenic Mice ◽

Vascular Function ◽

Vascular Dysfunction ◽

Critical Role ◽

Surrogate Marker ◽

Dominant Negative ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

PPARG, a ligand-activated transcription factor plays a critical role in the regulation of blood pressure and vascular function. We hypothesized that smooth muscle cell (SMC) PPARG protects against hypertension (HT) and resistance vessel dysfunction. Transgenic mice expressing dominant negative PPARG (S-P467L) in SMC or non-transgenic controls (NT) were implanted with DOCA pellet and allowed ad libitum access to 0.15 M NaCl for 21 days in addition to regular chow and water. Blood pressure was monitored by telemetry and mesenteric arterial (MA) function was assessed by pressurized myograph. At baseline, 24-hour mean arterial pressure (MAP) was similar between NT and S-P467L mice, while the transgenic mice were tachycardic. DOCA-salt increased MAP to a much greater degree in S-P467L mice (Δ MAP; S-P467L: +34.2±6.0, NT: +13.3±5.7, p<0.05 vs NT). Heart rate was similarly decreased in both groups after DOCA-salt. Vasoconstriction to KCl, phenylephrine and endothelin-1 did not differ in MA from DOCA-salt treated NT and S-P467L, while the response to vasopressin was significantly reduced in S-P467L after DOCA-salt (% constriction at 10-8 M, S-P467L: 31.6±5.6, NT: 46.7±3.8, p<0.05 vs NT). Urinary copeptin, a surrogate marker for arginine vasopressin was similar in both groups regardless of treatment. Vasorelaxation to acetylcholine was slightly impaired in S-P467L MA compared to NT at baseline whereas this effect was further exaggerated after DOCA-salt (% relaxation at 10-5 M, S-P467L: 56.1±8.3, NT: 79.4±5.6, p<0.05 vs NT). Vascular morphology at luminal pressure of 75 mmHg showed a significant increase in wall thickness (S-P467L: 18.7±0.8, NT: 16.0±0.4, p<0.05 vs NT) and % media/lumen (S-P467L: 8.4±0.3, NT: 7.1±0.2, p<0.05 vs NT) in S-P467L MA after DOCA-salt. Expression of tissue inhibitor of metalloproteinases (TIMP)-4 and regulator of G-protein signaling (RGS)-5 transcript were 2- and 3.5-fold increased, respectively, in MA of NT with DOCA-salt compared to NT baseline. However, this induction was markedly blunted in S-P467L MA. We conclude that interference with PPARG function in SMC leads to altered gene expression crucial for normal vascular homeostasis, thereby sensitizing the mice to the effects of DOCA-salt induced HT and vascular dysfunction.

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Interleukin-9 Deletion Relieves Vascular Dysfunction and Decreases Blood Pressure via the STAT3 Pathway in Angiotensin II-Treated Mice

Mediators of Inflammation ◽

10.1155/2020/5741047 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Yunzhao Yang ◽

Shaoqun Tang ◽

Chunchun Zhai ◽

Xin Zeng ◽

Qingjian Liu ◽

...

Keyword(s):

Blood Pressure ◽

Smooth Muscle ◽

Angiotensin Ii ◽

Inflammatory Response ◽

Vascular Dysfunction ◽

Control Group ◽

Dependent Manner ◽

Ang Ii ◽

Stat3 Pathway

Background. Multiple interleukin (IL) family members were reported to be closely related to hypertension. We aimed to investigate whether IL-9 affects angiotensin II- (Ang II-) induced hypertension in mice. Methods. Mice were treated with Ang II, and IL-9 expression was determined. In addition, effects of IL-9 knockout (KO) on blood pressure were observed in Ang II-infused mice. To determine whether the effects of IL-9 on blood pressure was mediated by the signal transducer and activator of the transcription 3 (STAT3) pathway, Ang II-treated mice were given S31-201. Furthermore, circulating IL-9 levels in patients with hypertension were measured. Results. Ang II treatment increased serum and aortic IL-9 expression in a dose-dependent manner; IL-9 levels were the highest in the second week and continued to remain high into the fourth week after the treatment. IL-9 KO downregulated proinflammatory cytokine expression, whereas it upregulated anti-inflammatory cytokine levels, relieved vascular dysfunction, and decreased blood pressure in Ang II-infused mice. IL-9 also reduced smooth muscle 22α (SM22α) expression and increased osteopontin (OPN) levels both in mice and in vitro. The effects of IL-9 KO on blood pressure and inflammatory response were significantly reduced by S31-201 treatment. Circulating IL-9 levels were significantly increased in patients with the hypertension group than in the control group, and elevated IL-9 levels positively correlated with both systolic blood pressure and diastolic blood pressure in patients with hypertension. Conclusions. IL-9 KO alleviates inflammatory response, prevents phenotypic transformation of smooth muscle, reduces vascular dysfunction, and lowers blood pressure via the STAT3 pathway in Ang II-infused mice. IL-9 might be a novel target for the treatment and prevention of clinical hypertension.

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Abstract 057: Nox5 Induces Vascular Dysfunction and Arterial Remodelling Independently of Blood Pressure Elevation in Ang II-infused Nox5-expressing Mice

Hypertension ◽

10.1161/hyp.68.suppl_1.057 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Augusto C Montezano ◽

Adam P Harvey ◽

Francisco J Rios ◽

Maria Dulak-Lis ◽

Wendy Beatie ◽

...

Keyword(s):

Blood Pressure ◽

Vascular Function ◽

Kinase Inhibitor ◽

Vascular Dysfunction ◽

Rho Kinase ◽

Lumen Diameter ◽

Ang Ii ◽

Cross Sectional ◽

Blood Pressure Elevation ◽

Endothelium Dependent Relaxation

Nox5 is a unique Ca 2+ -sensitive Nox isoform that is expressed in human vascular smooth muscle cells (VSMC). Although Nox5 has been implicated in diabetic nephropathy, its role in vascular function and development of hypertension remain unclear. Nox5 is not expressed in rodents, and accordingly we generated humanised Nox5 mice with Nox5 expressed in a VSMC-specific manner (Nox5SM22). Control (wild-type) and Nox5SM22 mice were infused with Ang II (600 ng/Kg/day). Blood pressure (BP) was assessed by tail-cuff. Vascular function and structure of resistance arteries were measured by myography. Ang II increased BP in WT (182.5±10 mmHg) and Nox5SM22 mice (173.1±5 mmHg) with no significant differences. Arteries from Nox5SM22 mice exhibited reduced endothelium-dependent relaxation versus WT controls (%ACh relaxation: 55.1±4 vs ctl: 81.6±7%). Fasudil (Rho kinase inhibitor)-induced relaxation was reduced in Nox5SM22 mice versus controls (%Fas: 111.3±11 vs ctl: 166.6±8%) (p<0.05). Ang II increased the maximal contraction to U46619 (thromboxane A2 mimetic) in WT (115.8±2 vs untreated: 101.4±2%) and Nox5SM22 (121.3±3 vs untreated: 99.1±2) (p<0.05) and induced endothelial dysfunction in all groups. Fasudil-induced relaxation was impaired by Ang II in WT (102.7±6 vs untreated: 166.6±8%, p<0.05) but not further impaired in Nox5SM22 mice (114.9±6 vs untreated: 111.3±11%). Ang II increased cross-sectional area (CSA) and lumen diameter; while in Nox5SM22 mice, Ang II increased wall thickness, wall-to-lumen ratio, CSA and decreased lumen diameter, with associated increased vascular stiffness. Our findings indicate that in mice expressing human Nox5 in VSMCs, endothelium-dependent relaxation is impaired, fasudil-mediated vasodilation is attenuated and vessels undergo exaggerated hypertrophic inward remodelling with increased stiffness; processes that occur independently of BP elevation. These data suggest an important role for Nox5 in Ang II-induced vascular dysfunction and remodeling, but not in the development of hypertension. Moreover, we identify Rho kinase as a putative target for Nox5-induced vascular injury. We provide novel insights into Nox5 vascular biology and demonstrate that vascular Nox5 actions are dissociated from BP effects.

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Influence of dietary inorganic nitrate on blood pressure and vascular function in hypertension: prospective implications for adjunctive treatment

Journal of Applied Physiology ◽

10.1152/japplphysiol.00371.2019 ◽

2019 ◽

Vol 127 (4) ◽

pp. 1085-1094 ◽

Cited By ~ 1

Author(s):

Ryan M. Broxterman ◽

D. Taylor La Salle ◽

Jia Zhao ◽

Van R. Reese ◽

Russell S. Richardson ◽

...

Keyword(s):

Blood Pressure ◽

Vascular Function ◽

Vascular Dysfunction ◽

Adjunctive Treatment ◽

Beetroot Juice ◽

Antihypertensive Medications ◽

Blood Pressure Elevation ◽

Inorganic Nitrate ◽

Plasma Nitrite ◽

Medication Status

Dietary inorganic nitrate (nitrate) is a promising adjunctive treatment to reduce blood pressure and improve vascular function in hypertension. However, it remains unknown if the efficacy of nitrate is dependent upon an elevated blood pressure or altered by medication in patients with hypertension. Therefore, blood pressure and vascular function, measured by passive leg movement (PLM) and flow-mediated dilation (FMD), were assessed following 3 days of placebo (nitrate-free beetroot juice) and nitrate (nitrate-rich beetroot juice) administration in 13 patients (age: 53 ± 12 yr) with hypertension taking antihypertensive medications ( study 1) and in 14 patients (49 ± 13 yr) with hypertension not taking antihypertensive medications ( study 2). In study 1, plasma nitrite concentration was greater for nitrate than placebo (341 ± 118 vs. 308 ± 123 nmol/L, P < 0.05), yet blood pressure and vascular function were unaltered. In study 2, plasma nitrite concentration was greater for nitrate than placebo (340 ± 102 vs. 295 ± 93 nmol/L, P < 0.01). Systolic (136 ± 16 vs. 141 ± 19 mmHg), diastolic (84 ± 13 vs. 88 ± 12 mmHg), and mean (101 ± 12 vs. 106 ± 13 mmHg) blood pressures were lower ( P < 0.05), whereas the PLM change in leg vascular conductance (6.0 ± 3.0 vs. 5.1 ± 2.6 mL·min−1·mmHg−1) and FMD (6.1 ± 2.4% vs. 4.1 ± 2.7%) were greater ( P < 0.05) for nitrate than placebo. The changes in systolic blood pressure ( r = −0.60) and FMD ( r = −0.48) induced by nitrate were inversely correlated ( P < 0.05) to the respective baseline values obtained in the placebo condition. Thus, the efficacy of nitrate to improve blood pressure and vascular function in hypertension appears to be dependent on the degree of blood pressure elevation and vascular dysfunction and not antihypertensive medication status, per se. NEW & NOTEWORTHY Dietary nitrate (nitrate) is a promising intervention to improve blood pressure and vascular function in hypertension. We demonstrate that these beneficial effects of nitrate are inversely related to the baseline value in a continuous manner with no distinction between antihypertensive medication status. Thus, the efficacy of nitrate to improve blood pressure and vascular function in hypertension appears to be dependent on the degree of blood pressure elevation and vascular dysfunction and not antihypertensive mediation status.

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The control of Ca2+ influx and NFATc3 signaling in arterial smooth muscle during hypertension

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0808759105 ◽

2008 ◽

Vol 105 (40) ◽

pp. 15623-15628 ◽

Cited By ~ 65

Author(s):

Madeline Nieves-Cintrón ◽

Gregory C. Amberg ◽

Manuel F. Navedo ◽

Jeffery D. Molkentin ◽

Luis F. Santana

Keyword(s):

Gene Expression ◽

Heart Failure ◽

Blood Pressure ◽

Smooth Muscle ◽

Vascular Dysfunction ◽

Signaling Cascade ◽

Myogenic Tone ◽

Excitable Cells ◽

Open Probability ◽

Induced Hypertension

Many excitable cells express L-type Ca2+ channels (LTCCs), which participate in physiological and pathophysiological processes ranging from memory, secretion, and contraction to epilepsy, heart failure, and hypertension. Clusters of LTCCs can operate in a PKCα-dependent, high open probability mode that generates sites of sustained Ca2+ influx called “persistent Ca2+ sparklets.” Although increased LTCC activity is necessary for the development of vascular dysfunction during hypertension, the mechanisms leading to increased LTCC function are unclear. Here, we tested the hypothesis that increased PKCα and persistent Ca2+ sparklet activity contributes to arterial dysfunction during hypertension. We found that PKCα and persistent Ca2+ sparklet activity is indeed increased in arterial myocytes during hypertension. Furthermore, in human arterial myocytes, PKCα-dependent persistent Ca2+ sparklets activated the prohypertensive calcineurin/NFATc3 signaling cascade. These events culminated in three hallmark signs of hypertension-associated vascular dysfunction: increased Ca2+ entry, elevated arterial [Ca2+]i, and enhanced myogenic tone. Consistent with these observations, we show that PKCα ablation is protective against the development of angiotensin II-induced hypertension. These data support a model in which persistent Ca2+ sparklets, PKCα, and calcineurin form a subcellular signaling triad controlling NFATc3-dependent gene expression, arterial function, and blood pressure. Because of the ubiquity of these proteins, this model may represent a general signaling pathway controlling gene expression and cellular function.

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Abstract P006: Liraglutide Attenuates Cardiac Fibrosis and Vascular Dysfunction in a Non-diabetic Angiotensin II-infusion Model via Anti-inflammatory and Anti-oxidant Mechanisms

Hypertension ◽

10.1161/hyp.66.suppl_1.p006 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Huey Wen Lee ◽

Melita Brdar ◽

Robert Widdop ◽

Anthony Dear ◽

Tracey Gaspari

Keyword(s):

Blood Pressure ◽

Vascular Function ◽

Cardiac Fibrosis ◽

Vascular Dysfunction ◽

Cardiomyocyte Hypertrophy ◽

High Dose ◽

Protective Effects ◽

Ang Ii ◽

Treatment Protocols ◽

Glucose Levels

Glucagon-like peptide-1 (GLP-1) based therapies are used to treat type II diabetes via increasing insulin secretion and inhibiting glucagon production. Recent evidence suggests that activating the GLP-1 receptor may also mediate direct vaso-protective effects. Therefore the objective of the study was to determine whether GLP-1R stimulation conferred cardio- and vaso-protection in a non-diabetic setting using the angiotensin (Ang) II infusion model of hypertension and cardiovascular dysfunction. Male C57Bl/6J mice (4-6 months) were assigned to one of the following 4 week treatment protocols: 1) vehicle (saline), 2) Ang II (800ng/kg/day), 3) Ang II + liraglutide (30μg/kg/day), 4) Ang II + liraglutide (300μg/kg/day). All treatments were administered via osmotic mini-pumps (s.c). After 4 weeks the effect of liraglutide treatment on blood pressure, vascular function and cardiac remodelling was examined. Liraglutide (both doses) attenuated Ang II-induced increase in systolic blood pressure (Ang II: 175.3 ± 8.6mmHg vs Ang II+Lirag (30) 150.2 ± 6.4 mmHg or Ang II+Lirag (300): 145.4 ± 6.9 mmHg) without affecting blood glucose levels. Liraglutide (both doses) completely prevented Ang II-induced endothelial dysfunction (% maximum relaxation: Ang II=50.7 ± 7.8%; Ang II+Lirag (30)=82.7 ± 5.8; Ang II+Lirag (300)=81.5 ± 6.1%). In the heart, liraglutide prevented Ang II-induced cardiomyocyte hypertrophy (n=7-10; p<0.05) and reduced collagen deposition (% collagen expression: Ang II=4.4 ± 0.5 vs Ang II+Lirag(300)=2.9 ± 0.3; n=7-9; p<0.01). This anti-fibrotic effect was attributed to reduced fibroblast/myofibroblast expression as well as decreased inflammation with reduced NFκB and MCP-1 expression and decreased oxidative stress with a significant reduction in superoxide production using high dose of liraglutide. Overall, stimulation of GLP-1R in a non-diabetic setting protected against Ang II-mediated cardiac hypertrophy, cardiac fibrosis and vascular dysfunction, indicating potential for use of GLP-1 based therapies in treatment of cardiovascular disease independent of diabetes.

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Abstract 14820: Sirt7 Deficiency in Blood Vessel Components Impairs Vascular Function by Inhibiting Cell Cycle- and Inflammatory-Related Protein Expression

Circulation ◽

10.1161/circ.132.suppl_3.14820 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Yuichi Kimura ◽

Yasuhiro Izumiya ◽

Satoshi Araki ◽

Satoru Yamamura ◽

Yoshiro Onoue ◽

...

Keyword(s):

Cell Proliferation ◽

Endothelial Cells ◽

Blood Flow ◽

Vascular Function ◽

Vascular Dysfunction ◽

Vascular Diseases ◽

Tube Formation ◽

Hindlimb Ischemia ◽

Proliferation Assay

Introduction: Aging is a well-established cardiovascular risk factor and associated with vascular dysfunction. Sirt7, one of the members of mammalian sirtuin family, is thought to be involved in age-related diseases. However, little is known about the relative contribution of Sirt7 in vascular dysfunction. Hypothesis: Sirt7 maintains vascular cell functions and its deficiency plays a critical role in vascular diseases. Methods: Sirt7 loss- and gain-of-function experiments were performed with human aortic smooth muscle cells (HAoSMCs) and human umbilical vein endothelial cells (HUVECs). In vivo, blood flow recovery was evaluated by hindlimb ischemia model in homozygous Sirt7 deficient (Sirt7-/-) and wild-type (WT) mice. Irradiated WT mice were intravenously received bone marrow (BM) cells from WT or Sirt7 -/- mouse to achieve BM transfer. Results: An RNAi-medicated Sirt7 knockdown resulted in a significant inhibition of HAoSMCs proliferation following serum or Platelet-derived growth factor BB (PDGF-BB) stimulation as determined by cell count, BrdU cell proliferation assay and MTS proliferation assay. Knockdown of endogenous Sirt7 also reduced cell migration as revealed by Boyden chamber migration assay. The Cyclin D1 and Cyclin dependent kinase 2 (CDK2) protein levels were significantly decreased in Sirt7 siRNA-treated HAoSMCs in response to serum or PDGF-BB stimulation. In endothelial cells, knockdown of Sirt7 attenuated tube formation, proliferation and migration. These changes were accompanied by reduced ERK activation and VCAM-1 mRNA and protein expression in Sirt7 siRNA-treated HUVECs. Conversely, overexpression of Sirt7 by adenovirus enhanced tube formation and cell proliferation. In vivo, blood flow recovery in response to hindlimb ischemia was significantly attenuated in Sirt7-/- mice compared with WT mice. There was no difference in blood flow recovery between WT mice transplanted with WT or Sirt7-/- BM cells suggesting that Sirt7 deficiency in vascular cells have a predominant effect on attenuated blood flow recovery in response to hindlimb ischemia. Conclusions: Sirt7 in blood vessel components have an important role in maintenance of vascular function. Sirt7 could be a promising therapeutic target for vascular diseases.

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Incorporation of platelet and leukocyte lipoxygenase metabolites by cultured vascular cells

Blood ◽

10.1182/blood.v67.2.373.373 ◽

1986 ◽

Vol 67 (2) ◽

pp. 373-378 ◽

Cited By ~ 27

Author(s):

AI Schafer ◽

H Takayama ◽

S Farrell ◽

MA Jr Gimbrone

Keyword(s):

Endothelial Cells ◽

Arachidonic Acid ◽

Smooth Muscle ◽

Fatty Acid ◽

Smooth Muscle Cells ◽

Vascular Function ◽

Muscle Cells ◽

Arachidonic Acid Metabolism ◽

Eicosatetraenoic Acid

Abstract When arachidonic acid metabolism is studied during platelet-endothelial interactions in vitro, the predominant cyclooxygenase end products of each cell type (thromboxane B2 and 6-keto-prostaglandin-F1 alpha, respectively) are essentially completely recovered in the cell-free supernatants of these reactions. In contrast, 50% of 12-hydroxy- 5,8,10,14-eicosatetraenoic acid (12-HETE), the major lipoxygenase metabolite from platelets, is released into the cell-free supernatant. In investigating the basis of this observation, we have found that platelet lipoxygenase metabolites were generated to the same extent during these coincubations but became rapidly incorporated into the endothelial cells. The endothelial cell-associated 12-HETE was present not only as free fatty acid, but was also incorporated into cellular phospholipids and triglycerides. When purified 3H-12-HETE, 3H-5-HETE (the major hydroxy acid lipoxygenase product of leukocytes), and 3H- arachidonic acid (the common precursor of these metabolites) were individually incubated with suspensions of cultured bovine aortic endothelial cells or smooth muscle cells, different patterns of intracellular lipid distribution were found. In endothelial cells, 12- HETE was incorporated equally into phospholipids and triglycerides, whereas 5-HETE was incorporated preferentially into triglycerides, and arachidonic acid was incorporated into phospholipids. In smooth muscle cells, both 12-HETE and 5-HETE showed more extensive incorporation into triglycerides. The rapid and characteristic incorporation and esterification of platelet and leukocyte monohydroxy fatty acid lipoxygenase products by endothelial and smooth muscle cells suggests a possible physiologic role for these processes in regulating vascular function.

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Rosiglitazone, a Ligand to PPARγ, Improves Blood Pressure and Vascular Function through Renin-Angiotensin System Regulation

PPAR Research ◽

10.1155/2019/1371758 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 7

Author(s):

María Sánchez-Aguilar ◽

Luz Ibarra-Lara ◽

Leonardo Del Valle-Mondragón ◽

María Esther Rubio-Ruiz ◽

Alicia G. Aguilar-Navarro ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

In Silico ◽

Vascular Function ◽

Renin Angiotensin System ◽

Dependent Manner ◽

Insulin Sensitizer ◽

Angiotensin System ◽

Renin Angiotensin

Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor gamma (PPARγ) ligand, has been reported to act as insulin sensitizer and exert cardiovascular actions. In this work, we hypothesized that RGZ exerts a PPARγ–dependent regulation of blood pressure through modulation of angiotensin-converting enzyme (ACE)-type 2 (ACE2)/angiotensin-(1-7)/angiotensin II type-2 receptor (AT2R) axis in an experimental model of high blood pressure. We carried on experiments in normotensive (Sham) and aortic coarctation (AoCo)-induced hypertensive male Wistar rats. Both sham and AoCo rats were treated 7 days with vehicle (V), RGZ (5 mg/kg/day), or RGZ+BADGE (120 mg/kg/day) post-coarctation. We measured blood pressure and vascular reactivity on aortic rings, as well as the expression of renin-angiotensin system (RAS) proteins. We found that RGZ treatment in AoCo group decreases blood pressure values and improves vascular response to acetylcholine, both parameters dependent on PPARγ-stimulation. RGZ lowered serum angiotensin II (AngII) but increased Ang-(1-7) levels. It also decreased 8-hydroxy-2′-deoxyguanosine (8-OH-2dG), malondialdehyde (MDA), and improved the antioxidant capacity. Regarding protein expression of RAS, RGZ decreases ACE and angiotensin II type 1 receptor (AT1R) and improved ACE2, AT2R, and Mas receptor in AoCo rats. Additionally, an in silico analysis revealed that 5′UTR regions of RAS and PPARγ share motifs with a transcriptional regulatory role. We conclude that RGZ lowers blood pressure values by increasing the expression of RAS axis proteins ACE2 and AT2R, decreasing the levels of AngII and increasing levels of Ang-(1-7) in a PPARγ-dependent manner. The in silico analysis is a valuable tool to predict the interaction between PPARγ and RAS.

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Glucose-6-phosphate dehydrogenase increases Ca2+ currents by interacting with Cav1.2 and reducing intrinsic inactivation of the L-type calcium channel

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00727.2019 ◽

2020 ◽

Vol 319 (1) ◽

pp. H144-H158 ◽

Cited By ~ 1

Author(s):

Rakhee Gupte ◽

Vidhi Dhagia ◽

Petra Rocic ◽

Rikuo Ochi ◽

Sachin A. Gupte

Keyword(s):

Blood Pressure ◽

Metabolic Syndrome ◽

Smooth Muscle ◽

Calcium Channel ◽

Smooth Muscle Cell ◽

Crucial Role ◽

Vascular Function ◽

Metabolic Enzyme ◽

Glucose 6 Phosphate Dehydrogenase ◽

Expression And Activity

In this study we have identified a novel isozyme of glucose-6-phosphate dehydrogenase (G6PD), a metabolic enzyme, that interacts with and contributes to regulate smooth muscle cell L-type Ca2+ ion channel function, which plays a crucial role in vascular function in physiology and pathophysiology. Furthermore, we demonstrate that expression and activity of this novel G6PD isoform are increased in arteries of individuals with metabolic syndrome and in inhibition of G6PD activity in rats of metabolic syndrome reduced blood pressure.

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