Abstract 228: CaMKII as a Link Between Inflammation and Fibrosis Induced by Chronic Isoproterenol and Angiotensin II Treatment

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Andrew Willeford ◽  
Joan Heller Brown
Keyword(s):  
Angiotensin Ii ◽  
Myocardial Injury ◽  
Cardiac Fibrosis ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Ang Ii ◽  
Cardiac Inflammation ◽  
Promising Therapeutic Target ◽  
Important Player ◽  
Camkii Activation

The Ca2+/calmodulin-dependent kinase, CaMKIIδ, is an established mediator of the development of heart failure and myocardial injury. Cardiac inflammation has been increasingly recognized as an important player in these cardiac pathophysiological changes. We previously demonstrated that CaMKIIδ contributes to cardiac inflammation induced by ischemia/reperfusion through activation of cardiomyocyte NF-kB. In the current study we ask whether angiotensin II (Ang II) and isoproterenol (ISO), both known to activate CaMKII, promote cardiac inflammation through this protein kinase and its effects on NF-kB activation. In addition, chronic ISO and Ang II treatment promote cardiac fibrosis and we hypothesize that this response is initiated through activation of CaMKIIδ and subsequent inflammatory responses. We report on our recent findings that show attenuated inflammatory cytokine expression (e.g. IL-6, MCP1, and TNFα) in response to 7 days Ang II infusion in mice in which CaMKIIδ is specifically deleted in cardiomyocytes (cardiac specific knockout; CKO). In addition the expression of fibrotic markers (e.g. col1a1, col3a1, and CTGF) in response to Ang II infusion is decreased in the CKO mice. This is associated with attenuated fibrosis as evident in histological analysis of CKO vs WT heart sections. Ongoing studies will compare the effects of chronic ISO and Ang II in CKO and WT mice to determine whether inflammation precedes fibrosis and assess the extent to which apoptosis induced by CaMKII activation plays a part in these responses. Currently, we are determining whether Ang II and ISO act through CaMKII to activate NF-kB in the cardiomyocyte compartment to induce proinflammatory and profibrotic factors and whether preventing the expression of these factors block development of further inflammatory and fibrotic responses. Findings from these studies may implicate CaMKII as a promising therapeutic target for attenuating cardiac fibrosis.

scholarly journals Adiponectin Suppresses Angiotensin II-Induced Inflammation and Cardiac Fibrosis through Activation of Macrophage Autophagy

Endocrinology ◽  
2014 ◽  
Vol 155 (6) ◽  
pp. 2254-2265 ◽  
Author(s):  
Guan-Ming Qi ◽  
Li-Xin Jia ◽  
Yu-Lin Li ◽  
Hui-Hua Li ◽  
Jie Du
Keyword(s):  
Angiotensin Ii ◽  
Protein Kinase ◽  
Cardiac Fibrosis ◽  
Inflammatory Responses ◽  
Smooth Muscle Actin ◽  
Underlying Mechanism ◽  
Nuclear Factor Κb ◽  
Ang Ii ◽  
Compound C

Previous studies have indicated that adiponectin (APN) protects against cardiac remodeling, but the underlying mechanism remains unclear. The present study aimed to elucidate how APN regulates inflammatory responses and cardiac fibrosis in response to angiotensin II (Ang II). Male APN knockout (APN KO) mice and wild-type (WT) C57BL/6 littermates were sc infused with Ang II at 750 ng/kg per minute. Seven days after Ang II infusion, both APN KO and WT mice developed equally high blood pressure levels. However, APN KO mice developed more severe cardiac fibrosis and inflammation compared with WT mice. This finding was demonstrated by the up-regulation of collagen I, α-smooth muscle actin, IL-1β, and TNF-α and increased macrophage infiltration in APN KO mice. Moreover, there were substantially fewer microtubule-associated protein 1 light chain 3-positive autophagosomes in macrophages in the hearts of Ang II-infused APN KO mice. Additional in vitro studies also revealed that globular APN treatment induced autophagy, inhibited Ang II-induced nuclear factor-κB activity, and enhanced the expression of antiinflammatory cytokines, including IL-10, macrophage galactose N-acetyl-galactosamine specific lectin 2, found in inflammatory zone 1, and type-1 arginase in macrophages. In contrast, APN-induced autophagy and antiinflammatory cytokine expression was diminished in Atg5-knockdown macrophages or by Compound C, an inhibitor of adenosine 5′-monophosphate-activated protein kinase. Our study indicates that APN activates macrophage autophagy through the adenosine 5′-monophosphate-activated protein kinase pathway and suppresses Ang II-induced inflammatory responses, thereby reducing the extent of cardiac fibrosis.

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.

THE ROLE OF CALCIUM (CA2+) IN MODULATION OF SMOOTH MUSCLE CELLS REACTIVITY TO ANGIOTENSIN II (ANG II) DURING ISCHEMIA/REPERFUSION (I/R).

2008 ◽  
Vol 86 (Supplement) ◽  
pp. 736
Author(s):  
M Slupski ◽  
K Szadujkis-Szadurska ◽  
R Szadujkis-Szadurski ◽  
M Jasinski ◽  
G Grzesk
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Smooth Muscle Cells ◽  
Ischemia Reperfusion ◽  
Muscle Cells ◽  
Ang Ii

scholarly journals SAT-562 Angiotensin II Induces Aldosterone Synthesis in the Rat Heart Stressed by Angiotensin II

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Himangshu S Bose ◽  
Randy M Whittal ◽  
Maheshinie Rajapaksha ◽  
Brendan Marshall ◽  
Ning-Ping Wang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Rat Heart ◽  
Mitochondrial Membrane ◽  
Myocardial Injury ◽  
Cardiac Fibrosis ◽  
De Novo ◽  
Regulatory Protein ◽  
Zona Glomerulosa ◽  
Inner Mitochondrial Membrane ◽  
Native Page

Abstract Aldosterone (Aldo) causes myocardial injury and fibrosis. While most Aldo is made by the adrenal zona glomerulosa; there have been controversial reports that Aldo is also synthesized in the heart; such myocardial synthesis of Aldo might contribute to myocardial injury. We induced cardiac fibrosis in rats by infusing angiotensin II (AngII) @ 500 ng/kg/min via subcutaneous pumps. After 4 weeks, circulating corticosterone increased about 400-fold from ~29 nM to ~11 μM. Aldo synthesis in isolated mitochondria (mito) was assessed by conversion of tritiated deoxycorticosterone to Aldo; AngII infusion doubled Aldo synthesis, and this augmented synthesis was inhibited in mito from rats receiving AngII + telmisartan, which inhibits the binding of AngII to the AT1 receptor. Western blotting showed P450c11AS (Aldo synthase) was also stimulated by AngII and inhibited by telmisartan in both rat heart and H9c2 myocardial cells. 2-dimentional native PAGE and mass spectrometry showed that a 290-kDa complex on the inner mitochondrial membrane (IMM) contained P450c11AS, Tom22 (a translocase associated with the outer mitochondrial membrane, OMM), and StAR (the steroidogenic acute regulatory protein). Immunocytochemistry and transmission electron microscopy monitoring of immune-gold particles confirmed that P450c11AS, Tom22, and StAR were associated with the mito, that P450c11AS and StAR were associated with the IMM and that P450c11AS and StAR, but not Tom22, were increased by AngII. Cardiac Aldo synthesis required myocardial expression of P450c11AS, but expression of P450scc, the initial steroidogenic enzyme that converts cholesterol to pregnenolone, was undetectable, indicating the heart cannot make Aldo de novo from cholesterol. The only known action of StAR is to promote the movement of cholesterol from the OMM to IMM; nevertheless, we found that intramitochondrial StAR is required for Aldo synthesis; protein crosslinking with BS3 showed that Tom22 forms a bridge between StAR and P450c11AS. This is the first activity ascribed to intramitochondrial StAR, but the manner by which StAR promotes P450c11AS activity is unclear. As P450scc was undetectable, and circulating concentrations of corticosterone approached the Km (~28 μM) for the use of corticosterone as a substrate for P450c11AS, we suggest that cardiac P450c11AS uses circulating steroids for substrate. Thus the stressed heart produces aldosterone using a previously undescribed intramitochondrial mechanism that involves P450c11AS, Tom22 and StAR

scholarly journals Angiotensin II Enhances Proliferation and Inflammation through AT1/PKC/NF-κB Signaling Pathway in Hepatocellular Carcinoma Cells

2016 ◽  
Vol 39 (1) ◽  
pp. 13-32 ◽  
Author(s):  
Yuanyuan Ji ◽  
Zhidong Wang ◽  
Zongfang Li ◽  
Aijun Zhang ◽  
Yaofeng Jin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Angiotensin Ii ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Hepatocyte Proliferation ◽  
Nuclear Antigen ◽  
Ang Ii ◽  
Hcc Cells

Background/Aims: The pathogenesis of hepatocellular carcinoma (HCC) is mainly characterized by persistent cycles of liver injury, inflammation, and compensatory hepatocyte proliferation. Angiotensin II (Ang II) behaves as an endogenous pro-inflammatory molecule playing a significant role in HCC, however, the molecular link between Ang II, proliferation and inflammation remains unclear. Methods: Human HCC cell lines (HepG-2, SMMC-7721, MHCC97-H) were incubated with Ang II at the indicated concentrations for 24, 48, 72 h. MTT, BrdU ELISA, plate colony formation assay, immunohistochemistry, ELISA, small-interfering RNA(siRNA) transfection, quantitative real-time PCR and western blot were applied to assess their functional, morphological and molecular mechanisms in HCC cell lines. Results: High expression of Ang II type 1 receptor (AT1) and low expression of AT2 in HCC cells and tissues were found. Next, Ang II could significantly enhance cell growth and proliferation. Albeit Ang II slightly increased the percentage of HCC cells in the G0/G1 phase using flow cytometry analysis, no statistically significant alterations were shown. Further studies suggested that Ang II could directly induce proliferation associated proteins C-myc and proliferating cell nuclear antigen (PCNA) expressions, and inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) productions in HCC cells. Interestingly, blocking AT1 and AT1 siRNA evidently inhibited Ang II-induced cell proliferation and inflammatory responses in HCC cells. More importantly, these effects may be mediated by AT1/PKC/NF-κB signaling pathway in HCC cell lines. Conclusions: The results propose that Ang II/AT1/PKC/NF-κB signaling pathway is necessary for proliferation and inflammation of HCC cells, which increases our understanding of the pathogenesis and provides clues for developing new strategies against Ang II-related progress of HCC.

scholarly journals Angiotensin II Removes Kidney Resistance Conferred by Ischemic Preconditioning

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Hee-Seong Jang ◽  
Jee In Kim ◽  
Jinu Kim ◽  
Jeen-Woo Park ◽  
Kwon Moo Park
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Ischemic Preconditioning ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Sham Operation ◽  
Kidney Fibrosis ◽  
Losartan Treatment

Ischemic preconditioning (IPC) by ischemia/reperfusion (I/R) renders resistance to the kidney. Strong IPC triggers kidney fibrosis, which is involved in angiotensin II (AngII) and its type 1 receptor (AT1R) signaling. Here, we investigated the role of AngII/AT1R signal pathway in the resistance of IPC kidneys to subsequent I/R injury. IPC of kidneys was generated by 30 minutes of bilateral renal ischemia and 8 days of reperfusion. Sham-operation was performed to generate control (non-IPC) mice. To examine the roles of AngII and AT1R in IPC kidneys to subsequent I/R, IPC kidneys were subjected to either 30 minutes of bilateral kidney ischemia or sham-operation following treatment with AngII, losartan (AT1R blocker), or AngII plus losartan. IPC kidneys showed fibrotic changes, decreased AngII, and increased AT1R expression. I/R dramatically increased plasma creatinine concentrations in non-IPC mice, but not in IPC mice. AngII treatment in IPC mice resulted in enhanced morphological damage, oxidative stress, and inflammatory responses, with functional impairment, whereas losartan treatment reversed these effects. However, AngII treatment in non-IPC mice did not change I/R-induced injury. AngII abolished the resistance of IPC kidneys to subsequent I/R via the enhancement of oxidative stress and inflammatory responses, suggesting that the AngII/AT1R signaling pathway is associated with outcome in injury-experienced kidney.

scholarly journals 5TNF-α and IL-1β Neutralization Ameliorates Angiotensin II-Induced Cardiac Damage in Male Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (7) ◽  
pp. 2677-2687 ◽  
Author(s):  
Yueli Wang ◽  
Yulin Li ◽  
Yina Wu ◽  
Lixin Jia ◽  
Jijing Wang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Adhesion Molecule ◽  
Cardiac Fibrosis ◽  
Smooth Muscle Actin ◽  
Cardiac Injury ◽  
Intercellular Adhesion Molecule ◽  
Ang Ii ◽  
Cardiac Damage ◽  
Inflammatory Infiltration ◽  
Tnf Α

Inflammation is a key event in hypertensive organ damage, and TNF-α and IL-1β are elevated in hypertension. In this study, we evaluated the effects of TNF-α and IL-1β elevation on hypertensive cardiac damage by treatment with a bifunctional inflammatory inhibitor, TNF receptor 2-fragment crystalization-IL-1 receptor antagonist (TFI), which can neutralize these 2 cytokines simultaneously. A mouse hypertension model of angiotensin II (Ang II) infusion (1500 ng/kg·min for 7 d) was induced in wild-type mice. TNF-α and IL-1β were inhibited by TFI administration (5 mg/kg, every other day), the effects of inhibition on cardiac damage were examined, and its mechanism on inflammatory infiltration was further studied in vivo and in vitro. Ang II infusion induced cardiac injury, including increased macrophage infiltration, expression of inflammatory cytokines (IL-12, IL-6, etc), and cardiac fibrosis, such as elevated α-smooth muscle actin, collagen I, and TGF-β expression. Importantly, the Ang II-induced cardiac injury was suppressed by TFI treatment. Moreover, TFI reduced the expression of adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) and monocyte chemotactic protein-1 expression in Ang II-treated hearts. Additionally, blockade of TNF-α and IL-1β by TFI reduced monocyte adherence to endothelia cell and macrophage migration. This study demonstrates that blocking TNF-α and IL-1β by TFI prevents cardiac damage in response to Ang II, and targeting these 2 cytokines simultaneously might be a novel tool to treat hypertensive heart injury.

scholarly journals Dual roles of chromatin remodeling protein BRG1 in angiotensin II-induced endothelial–mesenchymal transition

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Zilong Li ◽  
Xiaochen Kong ◽  
Yuanyuan Zhang ◽  
Yangxi Zhang ◽  
Liming Yu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Chromatin Remodeling ◽  
Cardiac Fibrosis ◽  
Vascular Endothelial Cells ◽  
Epigenetic Mechanism ◽  
Ang Ii ◽  
Dual Roles ◽  
Mesenchymal Transition ◽  
The One ◽  
Endothelial Mesenchymal Transition

Abstract Endothelial–mesenchymal transition (EndMT) is considered one of the processes underlying tissue fibrosis by contributing to the pool of myofibroblasts. In the present study, we investigated the epigenetic mechanism whereby angiotensin II (Ang II) regulates EndMT to promote cardiac fibrosis focusing on the role of chromatin remodeling protein BRG1. BRG1 knockdown or inhibition attenuated Ang II-induced EndMT, as evidenced by down-regulation of CDH5, an endothelial marker, and up-regulation of COL1A2, a mesenchymal marker, in cultured vascular endothelial cells. On the one hand, BRG1 interacted with and was recruited by Sp1 to the SNAI2 (encoding SLUG) promoter to activate SNAI2 transcription in response to Ang II stimulation. Once activated, SLUG bound to the CDH5 promoter to repress CDH5 transcription. On the other hand, BRG1 interacted with and was recruited by SRF to the COL1A2 promoter to activate COL1A2 transcription. Mechanistically, BRG1 evicted histones from the target promoters to facilitate the bindings of Sp1 and SRF. Finally, endothelial conditional BRG1 knockout mice (CKO) exhibited a reduction in cardiac fibrosis, compared to the wild type (WT) littermates, in response to chronic Ang II infusion. In conclusion, our data demonstrate that BRG1 is a key transcriptional coordinator programming Ang II-induced EndMT to contribute to cardiac fibrosis.

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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