scholarly journals Local Actions of Atrial Natriuretic Peptide Counteract Angiotensin II Stimulated Cardiac Remodeling

Endocrinology ◽  
2007 ◽  
Vol 148 (9) ◽  
pp. 4162-4169 ◽  
Author(s):  
Ana Kilić ◽  
Alexander Bubikat ◽  
Birgit Gaßner ◽  
Hideo A. Baba ◽  
Michaela Kuhn
Keyword(s):  
Angiotensin Ii ◽  
Knockout Mice ◽  
Growth Response ◽  
Chronic Administration ◽  
Ang Ii ◽  
Signal Transducers ◽  
Hypertrophic Growth ◽  
Brain Natriuretic Peptides ◽  
Cardiac Hormones

The cardiac hormones atrial and brain natriuretic peptides (NPs) counteract the systemic, hypertensive, and hypervolemic actions of angiotensin II (Ang II) via their guanylyl cyclase-A (GC-A) receptor. In the present study, we took advantage of genetically modified mice with conditional, cardiomyocyte (CM)-restricted disruption of GC-A (CM GC-A knockout mice) to study whether NPs can moderate not only the endocrine but also the cardiac actions of Ang II in vivo. Fluorometric measurements of [Ca2+]i transients in isolated, electrically paced adult CMs showed that atrial NP inhibits the stimulatory effects of Ang II on free cytosolic Ca2+ transients via GC-A. Remarkably, GC-A-deficient CMs exhibited greatly enhanced [Ca2+]i responses to Ang II, which was partly related to increased activation of the Na+/H+-exchanger NHE-1. Chronic administration of Ang II to control and CM GC-A knockout mice (300 ng/kg body weight per minute via osmotic minipumps during 2 wk) provoked significant cardiac hypertrophy, which was markedly exacerbated in the later genotype. This was concomitant to increased cardiac expression of NHE-1 and enhanced activation of the Ca2+/calmodulin-dependent prohypertrophic signal transducers Ca2+/calmodulin-dependent kinase II and calcineurin. On the basis of these results, we conclude that NPs exert direct local, GC-A-mediated myocardial effects to antagonize the [Ca2+]i-dependent hypertrophic growth response to Ang II.

scholarly journals Angiotensin II stimulates superoxide production in the thick ascending limb by activating NOX4

2012 ◽  
Vol 303 (7) ◽  
pp. C781-C789 ◽  
Author(s):  
Katherine J. Massey ◽  
Nancy J. Hong ◽  
Jeffrey L. Garvin
Keyword(s):  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Knockout Mice ◽  
Thick Ascending Limb ◽  
Ang Ii ◽  
Wild Type ◽  
Outer Medulla ◽  
Catalytic Subunits ◽  
In The Wild

Angiotensin II (ANG II) stimulates production of superoxide (O2−) by NADPH oxidase (NOX) in medullary thick ascending limbs (TALs). There are three isoforms of the catalytic subunit (NOX1, 2, and 4) known to be expressed in the kidney. We hypothesized that NOX2 mediates ANG II-induced O2− production by TALs. To test this, we measured NOX1, 2, and 4 mRNA and protein by RT-PCR and Western blot in TAL suspensions from rats and found three catalytic subunits expressed in the TAL. We measured O2− production using a lucigenin-based assay. To assess the contribution of NOX2, we measured ANG II-induced O2− production in wild-type and NOX2 knockout mice (KO). ANG II increased O2− production by 346 relative light units (RLU)/mg protein in the wild-type mice ( n = 9; P < 0.0007 vs. control). In the knockout mice, ANG II increased O2− production by 290 RLU/mg protein ( n = 9; P < 0.007 vs. control). This suggests that NOX2 does not contribute to ANG II-induced O2− production ( P < 0.6 WT vs. KO). To test whether NOX4 mediates the effect of ANG II, we selectively decreased NOX4 expression in rats using an adenovirus that expresses NOX4 short hairpin (sh)RNA. Six to seven days after in vivo transduction of the kidney outer medulla, NOX4 mRNA was reduced by 77%, while NOX1 and NOX2 mRNA was unaffected. In control TALs, ANG II stimulated O2− production by 96%. In TALs transduced with NOX4 shRNA, ANG II-stimulated O2− production was not significantly different from the baseline. We concluded that NOX4 is the main catalytic isoform of NADPH oxidase that contributes to ANG II-stimulated O2− production by TALs.

scholarly journals A new mechanism for the sex differences in angiotensin II-induced hypertension: the role of macula densa NOS1β-mediated tubuloglomerular feedback

2020 ◽  
Vol 319 (5) ◽  
pp. F908-F919
Author(s):  
Jie Zhang ◽  
Larry Qu ◽  
Jin Wei ◽  
Shan Jiang ◽  
Lan Xu ◽  
...  
Keyword(s):  
Sex Differences ◽  
Angiotensin Ii ◽  
Knockout Mice ◽  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Ang Ii ◽  
Wild Type ◽  
Induced Hypertension

Females are protected against the development of angiotensin II (ANG II)-induced hypertension compared with males, but the mechanisms have not been completely elucidated. In the present study, we hypothesized that the effect of ANG II on the macula densa nitric oxide (NO) synthase 1β (NOS1β)-mediated tubuloglomerular feedback (TGF) mechanism is different between males and females, thereby contributing to the sexual dimorphism of ANG II-induced hypertension. We used microperfusion, micropuncture, clearance of FITC-inulin, and radio telemetry to examine the sex differences in the changes of macula densa NOS1β expression and activity, TGF response, natriuresis, and blood pressure (BP) after a 2-wk ANG II infusion in wild-type and macula densa-specific NOS1 knockout mice. In wild-type mice, ANG II induced higher expression of macula densa NOS1β, greater NO generation by the macula densa, and a lower TGF response in vitro and in vivo in females than in males; the increases of glomerular filtration rate, urine flow rate, and Na+ excretion in response to an acute volume expansion were significantly greater and the BP responses to ANG II were significantly less in females than in males. In contrast, these sex differences in the effects of ANG II on TGF, natriuretic response, and BP were largely diminished in knockout mice. In addition, tissue culture of human kidney biopsies (renal cortex) with ANG II resulted in a greater increase in NOS1β expression in females than in males. In conclusion, macula densa NOS1β-mediated TGF is a novel and important mechanism for the sex differences in ANG II-induced hypertension.

Angiotensin II modulates frizzled-2 receptor expression in rat vascular smooth muscle cells

2005 ◽  
Vol 108 (6) ◽  
pp. 523-530 ◽  
Author(s):  
Giovanna CASTOLDI ◽  
Serena REDAELLI ◽  
Willy M. M. van de GREEF ◽  
Cira R. T. di GIOIA ◽  
Giuseppe BUSCA ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Ang Ii ◽  
Aortic Smooth Muscle

Ang II (angiotensin II) has multiple effects on vascular smooth muscle cells through the modulation of different classes of genes. Using the mRNA differential-display method to investigate gene expression in rat aortic smooth muscle cells in culture in response to 3 h of Ang II stimulation, we observed that Ang II down-regulated the expression of a member of the family of transmembrane receptors for Wnt proteins that was identified as Fzd2 [Fzd (frizzled)-2 receptor]. Fzds are a class of highly conserved genes playing a fundamental role in the developmental processes. In vitro, time course experiments demonstrated that Ang II induced a significant increase (P<0.05) in Fzd2 expression after 30 min, whereas it caused a significant decrease (P<0.05) in Fzd2 expression at 3 h. A similar rapid up-regulation after Ang II stimulation for 30 min was evident for TGFβ1 (transforming growth factor β1; P<0.05). To investigate whether Ang II also modulated Fzd2 expression in vivo, exogenous Ang II was administered to Sprague–Dawley rats (200 ng·kg−1 of body weight·min−1; subcutaneously) for 1 and 4 weeks. Control rats received normal saline. After treatment, systolic blood pressure was significantly higher (P<0.01), whereas plasma renin activity was suppressed (P<0.01) in Ang II- compared with the saline-treated rats. Ang II administration for 1 week did not modify Fzd2 expression in aorta of Ang II-treated rats, whereas Ang II administration for 4 weeks increased Fzd2 mRNA expression (P<0.05) in the tunica media of the aorta, resulting in a positive immunostaining for fibronectin at this time point. In conclusion, our data demonstrate that Ang II modulates Fzd2 expression in aortic smooth muscle cells both in vitro and in vivo.

Abstract MP03: ROCK2 Specific Inhibition Attenuates Angiotensin II-induced Hypertension In Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Daniel J Fehrenbach ◽  
Meena S Madhur
Keyword(s):  
Blood Pressure ◽  
T Cell ◽  
Angiotensin Ii ◽  
Repeated Measures ◽  
Flow Cytometric Analysis ◽  
Coiled Coil ◽  
Ang Ii ◽  
Induced Hypertension

Hypertension, or an elevated blood pressure, is the primary modifiable risk factor for cardiovascular disease, the number one cause of mortality worldwide. We previously demonstrated that Th17 activation and interleukin 17A (IL-17A)/IL-21 production is integral for the full development of a hypertensive phenotype as well as the renal and vascular damage associated with hypertension. Rho-associated coiled-coil containing protein Kinase 2 (ROCK2) serves as a molecular switch upregulating Th17 and inhibiting regulatory T cell (Treg) differentiation. We hypothesize that hypertension is characterized by excessive T cell ROCK2 activation leading to increased Th17/Treg ratios and ultimately end-organ damage. We first showed in vitro that KD025, an experimental orally bioavailable ROCK2 inhibitor inhibits Th17 cell proliferation and IL-17A/IL-21 production. To determine if hypertensive stimuli such as endothelial stretch increases T cell ROCK2 expression, we cultured human aortic endothelial cells exposed to 5% (normotensive) or 10% (hypertensive) stretch with circulating human T cells and HLA-DR+ antigen presenting cells. Hypertensive stretch increased T cell ROCK2 expression 2-fold. We then tested the effect of ROCK2 inhibition with KD025 (50mg/kg i.p. daily) in vivo on angiotensin II (Ang II)-induced hypertension. Treatment with KD025 significantly attenuated the hypertensive response within 1 week of Ang II treatment (systolic blood pressure: 139± 8 vs 108±7mmHg) and this persisted for the duration of the 4 week study reaching blood pressures 20 mmHg lower (135±13mmHg) than vehicle treated mice (158±4mmHg p<0.05 effect of treatment 2-way Repeated Measures ANOVA). Flow cytometric analysis of tissue infiltrating leukocytes revealed that KD025 treatment increased Treg/Th17 ratios in the kidney (0.61±0.03 vs 0.79±0.08, p<0.05 student’s t-test). Thus, T cell ROCK2 may be a novel therapeutic target for the treatment of hypertension.

Angiotensin II is associated with activation of NF-κB-mediated genes and downregulation of PPARs

2002 ◽  
Vol 11 (1) ◽  
pp. 21-30 ◽  
Author(s):  
Doris M. Tham ◽  
Baby Martin-McNulty ◽  
Yi-xin Wang ◽  
Dennis W. Wilson ◽  
Ronald Vergona ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Adhesion Molecule ◽  
Vascular Inflammation ◽  
Aortic Aneurysms ◽  
Intercellular Adhesion Molecule ◽  
Ang Ii ◽  
Inflammatory Genes ◽  
Apoe Ko Mice ◽  
Apoe Ko

Angiotensin II (ANG II) promotes vascular inflammation through nuclear factor-κB (NF-κB)-mediated induction of pro-inflammatory genes. The role of peroxisome proliferator-activated receptors (PPARs) in modulating vascular inflammation and atherosclerosis in vivo is unclear. The aim of the present study was to examine the effects of ANG II on PPARs and NF-κB-dependent pro-inflammatory genes in the vascular wall in an in vivo model of atherosclerosis and aneurysm formation. Six-month-old male apolipoprotein E-deficient (apoE-KO) mice were treated with ANG II (1.44 mg/kg per day for 30 days). ANG II enhanced vascular inflammation, accelerated atherosclerosis, and induced formation of abdominal aortic aneurysms. These effects of ANG II in the aorta were associated with downregulation of both PPAR-α and PPAR-γ mRNA and protein and an increase in transcription of monocyte chemotactic protein-1 (MCP-1), macrophage-colony stimulating factor (M-CSF), endothelial-selectin (E-selectin), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) throughout the entire aorta. ANG II also activated NF-κB with increases in both p52 and p65 NF-κB subunits. In summary, these in vivo results indicate that ANG II, through activation of NF-κB-mediated pro-inflammatory genes, promotes vascular inflammation, leading to acceleration of atherosclerosis and induction of aneurysm in apoE-KO mice. Downregulation of PPAR-α and -γ by ANG II may diminish the anti-inflammatory potential of PPARs, thus contributing to enhanced vascular inflammation.

scholarly journals Skeletal muscle-endothelial cell cross talk through angiotensin II

2010 ◽  
Vol 299 (6) ◽  
pp. C1402-C1408 ◽  
Author(s):  
Leeann M. Bellamy ◽  
Adam P. W. Johnston ◽  
Michael De Lisio ◽  
Gianni Parise
Keyword(s):  
Skeletal Muscle ◽  
Endothelial Cells ◽  
Cell Migration ◽  
Endothelial Cell ◽  
Angiotensin Ii ◽  
Branch Point ◽  
Endothelial Cell Migration ◽  
Tube Length ◽  
Ang Ii

The role of angiotensin II (ANG II) in postnatal vasculogenesis and angiogenesis during skeletal muscle (SKM) regeneration is unknown. We examined the capacity of ANG II to stimulate capillary formation and growth during cardiotoxin-induced muscle regeneration in ACE inhibitor-treated ANG II type 1a receptor knockout (AT1a−/−) and C57Bl/6 control mice. Analysis of tibialis anterior (TA) cross-sections revealed 17% and 23% reductions in capillarization in AT1a−/− and captopril treated mice, respectively, when compared with controls, 21 days postinjury. Conversely, no differences in capillarization were detected at early time points (7 and 10 days). These results identify ANG II as a regulator of angiogenesis but not vasculogenesis in vivo. In vitro angiogenesis assays of human umbilical vein endothelial cells (HUVECs) further confirmed ANG II as proangiogeneic as 71% and 124% increases in tube length and branch point number were observed following ANG II treatment. Importantly, treatment of HUVECs with conditioned media from differentiated muscle cells resulted in an 84% and 203% increase in tube length and branch point number compared with controls, which was abolished following pretreatment of the cells with an angiotensin-converting enzyme inhibitor. The pro-angiogenic effect of ANG II can be attributed to an enhanced endothelial cell migration because both transwell and under agarose migration assays revealed a 37% and 101% increase in cell motility, respectively. Collectively, these data highlight ANG II as a proangiogenic regulator during SKM regeneration in vivo and more importantly demonstrates that ANG II released from SKM can signal endothelial cells and regulate angiogenesis through the induction of endothelial cell migration.

Abstract 189: Natriuretic Peptide Receptor-A Regulates Angiotensin-II Mediated NF-κB Via Mkp-1 Dependent Pathway

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Gopi Venkatachalam ◽  
Umadevi Subramanian ◽  
Parthasarathy Arumugam ◽  
Elangovan Vellaichamy
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Nuclear Translocation ◽  
Heart Tissue ◽  
Male Rats ◽  
Natriuretic Peptide Receptor ◽  
Ang Ii ◽  
Hypertrophic Growth ◽  
Peptide Receptor

Atrial natriuretic peptide (ANP) exerts local anti-hypertrophic activity in heart tissue by binding to natriuretic peptide receptor (NPR)-A. However, patients with cardiac hypertrophy and congestive heart failure have elevated plasma and tissue levels of ANP and brain natriuretic peptide (BNP) along with Angiotensin II (Ang II). However, the rationale behind the impaired action of ANP in diseased state is not well understood. In this study, we sought to examine the signaling mechanism by which Ang II modulates local anti-hypertrophic effect through inhibition of Npr1 gene, which codes for NPR-A, in the heart. Hence, in vivo , Wistar male rats (n=8/group) were administered suppressor dose of Ang II (50ng/kg/min) for 14 days through implanted mini-osmotic pumps. Also, in vitro , H9C2 (2-1) cardio myofibroblast cells were exposed to Ang II (10 -7 M) for 20 hours. Upon treatment with Ang II, the mRNA and protein expression of Npr1 (p<0.01) was decreased with significant increase in expression of AT1R (p<0.01) in the heart tissues. In addition, a concomitant decrease in cGMP activity and production in isolated heart tissue membrane preparation was found in Ang II infused rats. Moreover, Ang II infusion causes a suppression of MKP-1 phosphatase; while enhancing the phosphorylation of ERK1/2 (p<0.01) and NF-κB (p<0.01) proteins. Similarly, H9C2 cells exhibited the hypertrophic growth with increased expression of AT1R and activation of ERK1/2 proteins on stimulation with Ang II. Furthermore, gene silencing using siRNA-NPR-A prior to Ang II treatment augmented the translocation of NF-κB and activation of ERK1/2 (3-fold). Whereas, pre-treatment with losartan or cGMP analog 8-Br-cGMP, an activator of cGMP-dependent protein kinases, abolished the stimulatory effects of Ang II on AT1R, NF-κB nuclear translocation and phosphorylation of MAPK, but activated the MKP-1 phosphatase. These results suggest that NPRA-cGMP signaling exerts inhibitory effects on Ang II by antagonizing the upstream signaling pathways and by activation of MKP-1 to counter-regulate NF-κB and MAPKs through cGMP dependent mechanism; thereby mediate local anti-hypertrophic activity in cardiac hypertrophy.

Abstract 229: TNF Receptor 1 Signaling Is Critically Involved in Mediating Angiotensin II-Induced Cardiac Fibrosis and Dysfunction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Sandra B Haudek ◽  
Jeff Crawford ◽  
Erin Reineke ◽  
Alberto A Allegre ◽  
George E Taffet ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Fibrosis ◽  
Smooth Muscle Actin ◽  
Protein A ◽  
Ang Ii ◽  
Wild Type ◽  
Monocyte Chemoattractant Protein 1 ◽  
Reactive Fibrosis

Angiotensin-II (Ang-II) plays a key role in the development of cardiomyopathies, as it is associated with many conditions involving heart failure and pathologic hypertrophy. Using a murine model of Ang-II infusion, we found that Ang-II induced the synthesis of monocyte chemoattractant protein 1 (MCP-1) that mediated the uptake of CD34 + /CD45 + monocytic cells into the heart. These precursor cells differentiated into collagen-producing fibroblasts and were responsible for the Ang-II-induced development of reactive fibrosis. Preliminary in vitro data using our monocyte-to-fibroblast differentiation model, suggested that Ang-II required the presence of TNF to induce fibroblast maturation from monocytes. In vivo, they indicated that in mice deficient of both TNF receptors (TNFR1 and TNFR2), Ang-II-induced fibrosis was absent. We now assessed the hypothesis that specific TNFR1 signaling is necessary for Ang-II-mediated cardiac fibrosis. Mice deficient in either TNFR1 (TNFR1-KO) or TNFR2 (TNFR2-KO) were subjected to continuous infusion of Ang-II for 1 to 6 weeks (n=6-8/group). Compared to wild-type, we found that in TNFR1-KO, but not in TNFR2-KO mouse hearts, collagen deposition was attenuated, as was cardiac α-smooth muscle actin protein (a marker for activated fibroblasts). When we isolated viable cardiac fibroblasts and characterized them by flow cytometry, we found that Ang-II infusion in TNFR1-KO, but not in TNFR2-KO, resulted in a marked decrease of CD34 + /CD45 + cells. Quantitative RT-PCR demonstrated a striking reduction of type 1 and 3 collagen, as well of MCP-1 mRNA expression in TNFR1-KO mouse hearts. Further measurements of cardiovascular parameters indicated that TNFR1-KO animals developed lesser Ang-II-mediated LV remodeling, smaller changes in E-linear deceleration times/rates over time, and displayed a lower Tei index (a heart rate independent marker of cardiac function), indicating less stiffness in TNFR1-KO hearts compared to wild-type and TNFR2-KO hearts. The data suggest that Ang-II-dependent cardiac fibrosis requires TNF and its signaling through TNFR1 which enhances the induction of MCP-1 and uptake of monocytic fibroblast precursors that are associated with reactive fibrosis and cardiac remodeling and function.

Abstract 598: Deletion of Microsomal PGE Synthase-1 Decreases Oxidative Stress and Protects Against Abdominal Aortic Aneurysm Formation in Angiotensin II-Infused Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Miao Wang ◽  
Jane Stubbe ◽  
Eric Lee ◽  
Wenliang Song ◽  
Emanuela Ricciotti ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
Density Lipoprotein Receptor ◽  
The Impact

Microsomal (m) prostaglandin (PG) E 2 synthase(S)-1, an enzyme that catalyzes the isomerization of the cyclooxygenase (COX) product, PGH 2 , into PGE 2 , is a major source of PGE 2 in vivo . mPGES-1 deletion in mice was found to modulate experimentally evoked pain and inflammation and atherogenesis is retarded in mPGES-1 knockout (KO) mice. The impact of mPGES-1 deletion on formation of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) was studied in mice lacking the low density lipoprotein receptor (LDLR −/− ). AngII infusion increased aortic macrophage recruitment and nitrotyrosine staining while upregulating both mPGES-1 and COX-2 and urinary excretion of the major metabolite of PGE 2 (PGE-M). Deletion of mPGES-1 decreased both the incidence and severity of AAA and depressed excretion of both PGE-M and 8, 12-iso-iPF 2a -VI, which reflects lipid peroxidation in vivo . While Ang II infusion augmented prostaglandin biosynthesis, deletion of mPGES-1 resulted in rediversion to PGD 2 , reflected by its major urinary metabolite. However, deletion of the PGD 2 receptor, DP1, did not affect AAA in Ang II infused LDLR −/− mice. These observations indicate that deletion of mPGES-1 protects against AAA formation by AngII in hyperlipidemic mice, perhaps by decreasing oxidative stress. Inhibition of mPGES-1 may represent an effective treatment to limit aneurysm occurrence and expansion.

Expression of Cell Cycle Proteins P21 waf1/Cip1 , P27 kip1 , Cyclin D1 and CDK4 in Blood Vessels of Angiotensin II-Infused Rats. Role of AT 1 Receptors.

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 707-707
Author(s):  
Quy N Diep ◽  
Mohammed El Mabrouk ◽  
Rhian M Touyz ◽  
Ernesto L Schiffrin
Keyword(s):  
Cell Cycle ◽  
Angiotensin Ii ◽  
Dna Synthesis ◽  
Cyclin D1 ◽  
Blood Vessels ◽  
Thymidine Incorporation ◽  
Mesenteric Arteries ◽  
Ang Ii

P79 Angiotensin II (Ang II) is an important modulator of cell growth via AT 1 receptors, as demonstrated both in vivo and in vitro . Here, we investigated the role of different proteins involved in the cell cycle, including cyclin D1, cyclin-dependent kinase 4 (cdk4) and cdk inhibitors p21 and p27 in blood vessels of Ang II-infused rats and the effect therein of the AT 1 receptor antagonist losartan. Male Sprague Dawley rats were infused for 7 days with Ang II (120 ng/kg/min s.c.) and/or treated with losartan (10 mg/kg/day orally). DNA synthesis in mesenteric arteries was evaluated by radiolabeled 3 H-thymidine incorporation. The expression of p21, p27, cyclin D1, cdk4 and E2F, which play critical roles during G1-phase of the cell cycle process, was examined by Western blot analysis. Tail cuff systolic blood pressure (mmHg) was elevated (p<0.05, n=9) in Ang II-infused rats (161.3±8.2) vs. controls (110.1±5.3) and normalized by losartan (104.4±3.2). Radiolabeled 3 H-thymidine incorporation (cpm/100 μg DNA) showed that Ang II-infusion significantly increased DNA synthesis (152±5 vs. 102±6, p<0.05). Expression of p21 and p27 was significantly decreased in the Ang II group to 23.2±10.4% and 10.3±5.3% of controls, respectively, whereas expression of cyclin D1 and cdk4 was significantly increased in the Ang II group to 213.7±8% and 263.6±37% of controls, respectively. These effects induced by Ang II infusion was normalized in the presence of losartan. Ang II had no effect on the expression of E2F. Thus, when AT 1 receptors are stimulated in vivo , DNA synthesis is enhanced in blood vessels by activation of cyclin D1 and cdk4. Reduction in cell cycle kinase inhibitors p21 and p27 may contribute to activation of growth induced by in vivo AT 1 receptor stimulation.

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