Abstract 456: Role of Signal Transducer and Activator of Transcription protein (STAT)-1 in the Angiotensin II-induced Cardiovascular Damage

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Stefan Chmielewski ◽  
Cristiane Aoqui ◽  
Hans Bluijssen ◽  
Marcus Baumann
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Mesenteric Arteries ◽  
Ang Ii ◽  
Independent Manner ◽  
Pressure Independent

Background: Inflammation participates importantly in hypertensive organ damage. Angiotensin II (Ang II) plays a crucial role in hypertension and induces inflammation. An essential mediator of inflammation is the transcription factor STAT1 which is activated by interferon but also by Ang II. We hypothesized that activation of STAT1 during Ang II infusion upregulates chemokines, enhances chemotaxis and consequently results in heart fibrosis and vessel dysfunction independent on blood pressure and hypertrophy Methods: C57BL/6, C57BL/6 receiving candesartan (5mg/kg) and STAT1-/- mice received infusion of Ang II 1.5 μg/g/day or placebo for 4 weeks (n=9/group). Blood pressure was measured using tail cuff pletysmography. Expression of chemokines Cxcl10, Cxcl9 and MCP-1 as well as Nos2 were investigated. Small mesenteric arteries (SMA) were mounted in a wire myograph to assess their function. Cardiac hypertrophy and inflammation (CD45 staining) and fibrosis (hydroxyproline assay) were determined. Results: Ang II caused expression of IFNg in C57BL/6 and STAT1-/- in vitro and in vivo. Blood pressure and cardiac hypertrophy did not differ between angiotensin treated C57BL/6 and STAT1-/- mice. Ang II increased in C57BL/6 expression of STAT1 dependent genes of chemokines and Nos2 (Cxcl10: 4.8-fold, Cxcl9: 3.4-fold, MCP-1: 6.6-fold, Nos2: 2.6-fold; all P<0.05) whereas this remained abolished in STAT1-/- mice. Ang II lead in STAT1-/- mice as compared to C57BL/6 to decreased cardiac CD45 number/view (C57BL/6-AngII: 27±4 STAT1-/--AngII: 11±5; P<0.05) and reduced cardiac fibrosis (hydroxyproline assay: C57BL/6-AngII: 80.6±11.8μmol/l versus STAT1-/- -AngII: 55.0±8.4μmol/l; P<0.05). Mesenteric arteries of STAT1-/- mice were fully protected against angiotensin induced endothelial dysfunction. Candesartan (AT1 receptor antagonist) inhibited action of Ang II in C57BL/6 and reduced but not reversed expression of chemokines in the heart. Conclusions: Lack of STAT1 revealed protection against Ang II-induced cardiac fibrosis and endothelial dysfunction. We suggest that STAT1-induced chemokine activation induces chemotaxis into hypertensive target organs and modifies cardiac fibrosis and vascular dysfunction in a blood pressure-independent manner.

scholarly journals Kaempferol Alleviates Angiotensin II-Induced Cardiac Dysfunction and Interstitial Fibrosis in Mice

2017 ◽  
Vol 43 (6) ◽  
pp. 2253-2263 ◽  
Author(s):  
Yuan Liu ◽  
Lu Gao ◽  
Sen Guo ◽  
Yuzhou Liu ◽  
Xiaoyan Zhao ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Neonatal Rat ◽  
Cardiac Remodelling ◽  
Ang Ii ◽  
Ventricular Fibrosis

Background/Aims: Endothelial-to-mesenchymal transition (EndMT) is a mechanism that promotes cardiac fibrosis induced by Angiotensin II (AngII). Kaempferol (KAE) is a monomer component mainly derived from the rhizome of Kaempferia galanga L. It shows anti-inflammatory, anti-oxidative, anti-microbial and anti-cancer properties, which can be used in the treatment of cancer, cardiovascular diseases, infection, etc. But, its effects on the development of cardiac remodelling remain completely unknown. The aim of the present study was to determine whether KAE attenuates cardiac hypertrophy induced by angiotensin II (Ang II) in cultured neonatal rat cardiac myocytes in vitro and cardiac hypertrophy induced by AngII infusion in mice in vivo. Methods: Male wild-type mice aged 8-10 weeks with or without KAE were subjected to AngII or saline, to induce fibrosis or as a control, respectively. Morphological changes, echocardiographic parameters, histological analyses, and hypertrophic markers were also used to evaluate hypertrophy. Results: KAE prevented and reversed cardiac remodelling induced by AngII. The KAE in this model exerted no basal effects but attenuated cardiac fibrosis, hypertrophy and dysfunction induced by AngII. Both in vivo and in vitro experiments demonstrated that Ang II infusion or TGF-β induced EndMT can be reduced by KAE and the proliferation and activation of cardiac fibroblasts (CFs) can be inhibited by KAE. Conclusions: The results suggest that KAE prevents and reverses ventricular fibrosis and cardiac dysfunction, providing an experimental basis for clinical treatment on ventricular fibrosis.

Capn4 aggravates angiotensin II-induced cardiac hypertrophy by activating the IGF-AKT signaling pathway

2021 ◽  
Author(s):  
Yuanping Cao ◽  
Qun Wang ◽  
Caiyun Liu ◽  
Wenjun Wang ◽  
Songqing Lai ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Expression Patterns ◽  
Akt Signaling ◽  
Calpain Inhibitor ◽  
Ang Ii ◽  
Akt Signaling Pathway ◽  
Calpain Activity

Abstract Capn4 belongs to a family of calpains that participate in a wide variety of biological functions, but little is known about the role of Capn4 in cardiac disease. Here, we show that the expression of Capn4 was significantly increased in Angiotensin II (Ang II)-treated cardiomyocytes and Ang II-induced cardiac hypertrophic mouse hearts. Importantly, in agreement with the Capn4 expression patterns, the maximal calpain activity measured in heart homogenates was elevated in Ang II-treated mice, and oral coadministration of SNJ-1945 (calpain inhibitor) attenuated the total calpain activity measured in vitro. Functional assays indicated that overexpression of Capn4 obviously aggravated Ang II-induced cardiac hypertrophy, whereas Capn4 knockdown resulted in the opposite phenotypes. Further investigation demonstrated that Capn4 maintained the activation of the insulin-like growth factor (IGF)-AKT signaling pathway in cardiomyocytes by increasing c-Jun expression. Mechanistic investigations revealed that Capn4 directly bound and stabilized c-Jun, and knockdown of Capn4 increased the ubiquitination level of c-Jun in cardiomyocytes. Additionally, our results demonstrated that the antihypertrophic effect of Capn4 silencing was partially dependent on the inhibition of c-Jun. Overall, these data suggested that Capn4 contributes to cardiac hypertrophy by enhancing the c-Jun-mediated IGF-AKT signaling pathway and could be a potential therapeutic target for hypertrophic cardiomyopathy.

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.

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.

scholarly journals Deficiency of T-type Ca2+ channels Cav3.1 and Cav3.2 has no effect on angiotensin II-induced hypertension but differential effect on plasma aldosterone in mice

2019 ◽  
Vol 317 (2) ◽  
pp. F254-F263
Author(s):  
Anne D. Thuesen ◽  
Stine H. Finsen ◽  
Louise L. Rasmussen ◽  
Ditte C. Andersen ◽  
Boye L. Jensen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Mineralocorticoid Receptor ◽  
Plasma Aldosterone ◽  
Receptor Blocker ◽  
Ang Ii ◽  
Induced Hypertension

T-type Ca2+ channel Cav3.1 promotes microvessel contraction ex vivo. It was hypothesized that in vivo, functional deletion of Cav3.1, but not Cav3.2, protects mice against angiotensin II (ANG II)-induced hypertension. Mean arterial blood pressure (MAP) and heart rate were measured continuously with chronically indwelling catheters during infusion of ANG II (30 ng·kg−1·min−1, 7 days) in wild-type (WT), Cav3.1−/−, and Cav3.2−/− mice. Plasma aldosterone and renin concentrations were measured by radioimmunoassays. In a separate series, WT mice were infused with ANG II (100 ng·kg−1·min−1) with and without the mineralocorticoid receptor blocker canrenoate. Cav3.1−/− and Cav3.2−/− mice exhibited no baseline difference in MAP compared with WT mice, but day-night variation was blunted in both Cav3.1 and Cav3.2−/− mice. ANG II increased significantly MAP in WT, Cav3.1−/−, and Cav3.2−/− mice with no differences between genotypes. Heart rate was significantly lower in Cav3.1−/− and Cav3.2−/− mice compared with control mice. After ANG II infusion, plasma aldosterone concentration was significantly lower in Cav3.1−/− compared with Cav3.2−/− mice. In response to ANG II, fibrosis was observed in heart sections from both WT and Cav3.1−/− mice and while cardiac atrial natriuretic peptide mRNA was similar, the brain natriuretic peptide mRNA increase was mitigated in Cav3.1−/− mice ANG II at 100 ng/kg yielded elevated pressure and an increased heart weight-to-body weight ratio in WT mice. Cardiac hypertrophy, but not hypertension, was prevented by the mineralocorticoid receptor blocker canrenoate. In conclusion, T-type channels Cav3.1and Cav3.2 do not contribute to baseline blood pressure levels and ANG II-induced hypertension. Cav3.1, but not Cav3.2, contributes to aldosterone secretion. Aldosterone promotes cardiac hypertrophy during hypertension.

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

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
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.

scholarly journals Protease-Activated Receptor 1 Contributes to Angiotensin II-Induced Cardiovascular Remodeling and Inflammation

Cardiology ◽  
2016 ◽  
Vol 136 (4) ◽  
pp. 258-268 ◽  
Author(s):  
Silvio Antoniak ◽  
Jessica C. Cardenas ◽  
Laura J. Buczek ◽  
Frank C. Church ◽  
Nigel Mackman ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Heart Function ◽  
Coronary Vessels ◽  
Wall Thickening ◽  
Ang Ii ◽  
Cardiovascular Remodeling ◽  
Protease Activated Receptor 1 ◽  
Pressure Independent ◽  
Fractional Shortening

Background: Angiotensin II (Ang II) plays an important role in cardiovascular disease. It also leads to the activation of coagulation. The coagulation protease thrombin induces cellular responses by activating protease-activated receptor 1 (PAR-1). We investigated whether PAR-1 contributes to Ang II-induced cardiovascular remodeling and inflammation. Methods and Results: PAR-1+/+ (wild-type; WT) and PAR-1-/- mice were infused with Ang II (600 ng/kg/min) for up to 4 weeks. In WT mice, this dose of Ang II did not cause a significant increase in blood pressure but it did cause pathological changes in both the aorta and the heart. Ang II infusion resulted in vascular remodeling of the aorta, demonstrated by a significant increase in medial wall thickening and perivascular fibrosis. Importantly, both parameters were significantly attenuated by PAR-1 deficiency. Furthermore, perivascular fibrosis around coronary vessels was reduced in Ang II-treated PAR-1-/- mice compared to WT mice. In addition, PAR-1 deficiency significantly attenuated Ang II induction of inflammatory cytokines and profibrotic genes in the aortas compared to WT mice. Finally, PAR-1 deficiency had no effect on Ang II-induced heart hypertrophy. However, the heart function measured by fractional shortening was less impaired in PAR-1-/- mice than in WT mice. Conclusion: Our data indicate that PAR-1 plays a significant role in cardiovascular remodeling mediated by a blood pressure-independent action of Ang II.

scholarly journals Autophagy inhibition by chloroquine prevents increase in blood pressure and preserves endothelial functions

2020 ◽  
Vol 19 (4) ◽  
pp. 789-796
Author(s):  
Moon Jain ◽  
Hina Iqbal ◽  
Pankaj Yadav ◽  
Himalaya Singh ◽  
Debabrata Chanda ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cell Migration ◽  
Endothelial Cell ◽  
Angiotensin Ii ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Autophagy Flux ◽  
Endothelial Functions

Purpose: To determine the effects of lysosomal inhibition of autophagy by chloroquine (CHQ) onhypertension-associated changes in the endothelial functions. Method: Angiotensin II (Ang II)-treated human endothelial cell line EA.hy926 and renovascularhypertensive rats were subjected to CHQ treatment (in vitro: 0.5, 1, and 2.5 μM; in vivo: 50 mg/kg/dayfor three weeks). Changes in the protein expressions of LC3b II (autophagosome formation marker) andp62 (autophagy flux marker) were assessed using immunoblotting. Cell migration assay, tubuleformation assay (in vitro), and organ bath studies (in vivo) were performed to evaluate the endothelialfunctions. Hemodynamic parameters were measured as well. Results: A higher expression of LC3b II and a reduced expression of p62 observed in the Ang II-treatedendothelial cells, as well as in the aorta of the hypertensive rats, indicated enhanced autophagy.Treatment with CHQ resulted in reduced autophagy flux (in vitro as well as in vivo) and suppressed AngII-induced endothelial cell migration and angiogenesis (in vitro). The treatment with CHQ was alsoobserved to prevent increase in blood pressure in hypertensive rats and preserved acetylcholineinducedrelaxation in phenylephrine-contracted aorta from the hypertensive rats. In addition, chloroquineattenuated Ang II-induced contractions in the aorta of normotensive as well as hypertensive rats. Conclusion: These observations indicated that CHQ lowers the blood pressure and preserves thevascular endothelial function during hypertension. Keywords: Angiotensin II, Autophagy, Chloroquine, Endothelial function, Hypertension, Vasculardysfunction

Abstract 101: Cardiac Deleterious Role of Galectin-3 in Chronic Angiotensin-II Induced Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Germán E González ◽  
Nour-Eddine Rhaleb ◽  
Xiao- P Yang ◽  
Oscar A Carretero
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Cardiac Fibrosis ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Carbohydrate Binding ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Galectin 3

We previously described that chronic infusion with Angiotensin II (Ang II) increases cardiac Galectin-3 (Gal-3) expression, a carbohydrate-binding lectin present on macrophages. Also, Gal-3 was proposed to be a powerful predictor for mortality in patients with heart failure. Nevertheless, the role of Gal-3 in the pathogenesis of end organ damage (EOD) in hypertension is unknown. Here, we hypothesized that in Ang II-induced hypertension, genetic deletion of Gal-3 prevents innate immunity, EOD, and left ventricular (LV) dysfunction. Male C57 and Gal-3 KO mice were infused with vehicle (V) or Ang II (90 ng/min; s.c.) for 8 weeks and divided into: 1) C57 + V; 2) Gal-3 KO + V; 3) C57 + Ang II and 4) Gal-3 KO + Ang II. Systolic blood pressure (SBP) was measured by plestimography weekly. At 8 week, we evaluated 1) LV ejection fraction (EF) by echocardiography; 2) cardiac hypertrophy by LV weight/tibia length; 3) cardiac fibrosis by picrosirius red staining; 4) infiltrated macrophages by CD68+ staining; 5) ICAM-1 protein expression by Western blot; and 6) serum interleukin (IL)-6 by ELISA. We found that despite a similar increase in SBP and LV hypertrophy in both strains on Ang II, Gal-3 KO mice had better reserved EF and decreased inflammatory and fibrotic responses (see Table). Results: (MEAN ± SEM at 8 w) *p<0.05 C57+Ang II and Gal-3 KO+Ang II vs C57+V; ‡ p<0.05 Gal-3 KO+Ang II vs C57+Ang II. Conclusion: In Ang II-induced hypertension, deletion of Gal-3 prevents EOD and LV systolic dysfunction without altering blood pressure and LV hypertrophy. This study indicates that the deleterious effects of Ang II could be in part mediated by Gal-3, which enhanced inflammation and fibrosis.

Abstract 215: Angiotensin-II-induced Cardiac Remodeling is Reduced in TNFR1-deficient Mice Despite Increased Blood Pressure

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Clemens Duerrschmid ◽  
Fernando Aguirre-Amezquite ◽  
George E Taffet ◽  
Mark L Entman ◽  
Sandra B Haudek
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Cardiac Function ◽  
Cardiac Fibrosis ◽  
Weight Ratio ◽  
Heart Weight ◽  
Ang Ii ◽  
Long Term Effects ◽  
2D Echocardiography ◽  
Collagen Iii

Background: Infusion of angiotensin-II (Ang-II) to wild-type (WT) mice results in hypertension, development of interstitial cardiac fibrosis and hypertrophy, and deterioration of myocardial function. We previously showed that after 1 week of Ang-II infusion, these effects were absent in mice deficient in tumor necrosis factor receptor 1 (TNFR1). We now investigated long-term effects of Ang-II infusion. Methods: WT and TNFR1-KO mice were infused with Ang-II for 6 weeks. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography; cardiac function by 2D-echocardiography and Doppler ultrasound. Hearts were analyzed for collagen deposition (histology) and expression of fibrosis- and hypertrophy- related genes (quantitative PCR). Results: In WT mice, SBP increased within 7 days and remained elevated at 6 weeks (152±4 mmHg); cardiac fibrosis developed after 1 week and persisted at 6 weeks (6.2±1.1% collagen area). By contrast, in TNFR1-KO mice, SBP at 7 days was low, but increased by 6 weeks (144±4 mmHg), whereas cardiac fibrosis was absent at 1 week and did not significantly increase by 6 weeks (2.5±0.5%). In support of these data, collagen I and collagen III mRNA expression at 6 weeks were upregulated in WT (2.9±0.6 and 4.1±0.8 -fold over sham), but not in TNFR1-KO hearts (1.3±0.1 and 1.8±0.2). In both mouse groups, cardiac hypertrophy and cardiac dysfunction developed over time, however, these changes were less prominent in TNFR1-KO mice: at 6 weeks, the heart-weight to body-weight ratio in WT was 6.7±0.4, in TNFR1-KO mice 5.5±0.2; the changes in anterior and posterior wall thicknesses in WT were 44±12% and 32±15%, in TNFR1-KO mice 19±8% and 17±10%; the change in ejection fraction in WT was -67±12%, in TNFR1-KO mice -39±5%; and the change in Tei-index (myocardial performance) in WT was 18±9%, in TNFR1-KO -1±7%. Also, hypertrophy-related atrial natriuretic peptide (ANP) and beta-myosin heavy chain (b-MHC) mRNA were upregulated in WT (4.3±0.9 and 4.3±0.6 -fold over sham), but less in TNFR1-KO hearts (2.6±0.5 and 2.4±0.5). Conclusion: Despite a significant increase in blood pressure over 6 weeks of Ang-II infusion, TNFR1-KO mice developed less cardiac fibrosis and hypertrophy and had better cardiac function compared to WT mice.

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