Abstract 19953: Interactions of MyD88 and TRIF-Pathways of Innate Immune Responses Regulate Angiotensin II Hypertension

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Madhu V Singh ◽  
Michael Z Cicha ◽  
Mark W Chapleau ◽  
François M Abboud
Keyword(s):  
Angiotensin Ii ◽  
Inflammatory Responses ◽  
Pressor Response ◽  
Alternative Pathway ◽  
Weight Ratio ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Innate Immune ◽  
Heart Weight ◽  
Ang Ii

We have reported that angiotensin II (Ang II) induces toll-like receptors (TLRs) in the innate immune system. Here we tested which of the two major adaptor proteins of TLRs, the myeloid differentiation protein 88 (MyD88) or the TIR-domain containing adaptor inducing interferon β (TRIF) mediates the Ang II-induced responses. Infusion of Ang II (3000 ng/kg/min) subcutaneously for 3 weeks in WT mice (C57BL/6J) increased systolic blood pressure to a peak value of 147 ± 4 mm Hg and resulted in a 40% increase in heart weight to body weight ratio (HW/BW). Surprisingly, in MyD88-/- mice the pressor response was enhanced significantly to 163 ± 6 mm Hg (P<0.05) and the HW/BW was increased by 60%. Cardiac and renal RNA expression of TNF-α, NOX4 and Type IA -Ang II receptor were also significantly more elevated in MyD88-/- than in WT. In contrast, in a mouse strain with nonfunctional TRIF gene, Trifmut (C57BL/6J-Ticam1Lps2/J), all the Ang II responses were either uniformly decreased or abrogated. We tested whether the enhanced response in MyD88-/- mice represented a phenomenon of ‘Signaling Flux Redistribution” whereby blockade of one signaling pathway (i.e., MyD88) results in a flux of signaling substrates through the alternative pathway (TRIF). We found that expression of the RNA for chemokine CXCL10 which is dependent on TRIF pathway, was significantly enhanced in MyD88-/- hearts. We also found that expression of transcripts for TLR3, TLR4 and the TRIF adaptor protein were all enhanced in MyD88-/- and must have contributed to the exaggerated Ang II response. Conversely, Trifmut had enhanced MyD88 expression. These results suggest that: (1) Ang II induced hypertension, hypertrophy and inflammatory gene expression are primarily mediated by the TRIF pathway and (2) the MyD88 pathway is simultaneously activated by Ang II and exerts a negative regulatory influence on the pressor and inflammatory responses. We conclude that dual activation of two innate immune pathways defines the net response in WT mice with a significant translational potential. Accordingly, impairment of MyD88 may contribute to pathogenesis of hypertension. Conversely, targeting the TRIF pathway may be therapeutic by blocking the inflammatory response and enhancing the negative regulatory effects of MyD88.

Dissociation of Direct and Indirect Effects of Angiotensin II on the Heart

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 683-684
Author(s):  
Jorge P van Kats ◽  
David W Silversides ◽  
Timothy L Reudelhuber
Keyword(s):  
Heart Rate ◽  
Angiotensin Ii ◽  
Systolic Pressure ◽  
Weight Ratio ◽  
Renin Angiotensin System ◽  
Cardiac Cells ◽  
Heart Weight ◽  
Ang Ii ◽  
Direct Stimulation ◽  
Beneficial Effects

33 Cardiac angiotensin II (Ang II), either derived from the circulation or locally synthesized, is often suggested to be involved in the structural adaptations occurring in the heart in hypertension and following myocardial infarction. However, it is debated whether the proven beneficial effects of renin-angiotensin system blockade in these pathologies are related to an inhibition of the direct cardiac actions of the peptide. The objective of the present study was to investigate which of the effects of cardiac Ang II are due to direct stimulation of cardiac cells by Ang II. To test for cardiac specific functions of Ang II, transgenic mice were developed that express an Ang II-releasing fusion protein (J Biol Chem 1997;272:12994-99) exclusively in cardiomyocytes. Blood pressure, heart rate, cardiac and plasma Ang II content, Ang II receptor binding and organ morphology were monitored in transgenic (TG) and non-transgenic littermate mice (control). Cardiac Ang II levels in TG mice were 20-40 fold higher than in hearts of control mice (15±3 pg/100 mg ww). In 3 independent founder lines of TG mice, plasma Ang II concentration was not altered as compared to control (119±20 vs. 127±20 pg/mL). The heart weight to body weight ratio in TG mice (4.0±0.1 mg/g) was not different from controls (3.8±0.1 mg/g), neither was systolic pressure (137±4 and 138±7 mm Hg respectively) or heart rate (618±13 and 662±15 bpm respectively). Microscopic inspection of TG hearts did not reveal any differences with control regarding size and number of cardiomyocytes and organization of extracellular matrix proteins. TG mice had not become less sensitive for Ang II signaling since Ang II receptor number was not altered in TG mice (Bmax = 23±3 fmol/mg protein) as compared to control (22±2 fmol/mg protein). Our data show that very high Ang II levels in hearts of TG mice do not lead to myocardial enlargement or affect cardiovascular physiology. We conclude that elevated Ang II in the heart has no direct effects on cardiac cells and we hypothesize that effects of cardiac Ang II become apparent upon altered hemodynamic loading.

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.

Abstract 072: TRIF-Pathway of Innate Immune Responses Mediates Angiotensin II Hypertension

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Madhu V Singh ◽  
Michael Z Cicha ◽  
Mark W Chapleau ◽  
François M Abboud
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Pressor Response ◽  
Weight Ratio ◽  
Negative Regulator ◽  
Heart Weight ◽  
Ang Ii ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Induced Hypertension

We tested the role of two distinct adaptors of toll-like receptor (TLR) signaling on Ang II-induced hypertension and cardiac hypertrophy. These TLR adaptors, myeloid differentiation protein 88 (MyD88) and TIR domain-containing adaptor inducing interferon β (TRIF) facilitate distinct inflammatory signaling pathways. In an earlier study, we reported that MyD88-/- mice are protected from cardiac hypertrophy and pro-inflammatory gene expression after myocardial infarction. Our current results with 3 weeks infusion of Ang II (3000 ng/kg/min) vs. saline indicate that in MyD88-/- mice, the pressor response to Ang II and cardiac hypertrophy were increased more than in wild type (WT) mice. In Ang II-infused WT, systolic blood pressure (SBP) peaked at 147 ± 4 mmHg whereas in Ang II-infused MyD88-/- mice SBP reached a peak value of 163 ± 6 mmHg. However, in mice with non-functional TRIF adaptor mutant (Trifmut), SBP did not increase during Ang II infusion and remained similar to the SBP in saline-infused mice (115 ± 3 mmHg). Baseline SBP was not different among WT, MyD88-/- and Trifmut mice. The increase in heart weight to body weight ratio (HW/BW) between saline and Ang II-infused mice was greater in MyD88-/- mice than WT mice (60% increase in MyD88-/- vs. 40% increase in WT), whereas it was less in Trifmut mice (22% increase). Accordingly, expression of several inflammatory genes (Tnfa, Nox4 and Agtr1a) was significantly greater (P< 0.05) in the heart and kidney of Ang II-infused MyD88-/- mice compared with Ang II-infused WT mice, whereas expression of these genes in Trifmut mice was either unchanged or reduced. We conclude that- (1) Ang II-induced hypertension, cardiac hypertrophy and inflammatory gene expression are mediated by activation of a TRIF-dependent pathway, but not by the MyD88-dependent pathways, and (2) Enhanced Ang II effects on SBP and hypertrophy in MyD88-/- mice suggest that MyD88 may serve as a negative regulator of the TRIF pathway in Ang II-induced hypertension. Selective targeting of these adaptor proteins may have significant therapeutic implications.

scholarly journals Angiotensin II-induced hypertension and cardiac hypertrophy are differentially mediated by TLR3- and TLR4-dependent pathways

2019 ◽  
Vol 316 (5) ◽  
pp. H1027-H1038 ◽  
Author(s):  
Madhu V. Singh ◽  
Michael Z. Cicha ◽  
Sarah Nunez ◽  
David K. Meyerholz ◽  
Mark W. Chapleau ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Innate Immune System ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Ang Ii ◽  
Interferon Β ◽  
Induced Hypertension ◽  
Deficient Mice ◽  
Receptor Domain

Toll-like receptors (TLR) are key components of the innate immune system that elicit inflammatory responses through the adaptor proteins myeloid differentiation protein 88 (MyD88) and Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF). Previously, we demonstrated that TRIF mediates the signaling of angiotensin II (ANG II)- induced hypertension and cardiac hypertrophy. Since TRIF is activated selectively by TLR3 and TLR4, our goals in this study were to determine the roles of TLR3 and TLR4 in mediating ANG II-induced hypertension and cardiac hypertrophy, and associated changes in proinflammatory gene expression in heart and kidney. In wild-type (WT) mice, ANG II infusion (1,000 ng·kg−1·min−1 for 3 wk) increased systolic blood pressure and caused cardiac hypertrophy. In ANG II-infused TLR4-deficient mice ( Tlr4del), hypertrophy was significantly attenuated despite a preserved or enhanced hypertensive response. In contrast, in TLR3-deficient mice ( Tlr3−/−), both ANG II-induced hypertension and hypertrophy were abrogated. In WT mice, ANG II increased the expression of several proinflammatory genes in hearts and kidneys that were attenuated in both TLR4- and TLR3-deficient mice compared with WT. We conclude that ANG II activates both TLR4-TRIF and TLR3-TRIF pathways in a nonredundant manner whereby hypertension is dependent on activation of the TLR3-TRIF pathway and cardiac hypertrophy is dependent on both TLR3-TRIF and TLR4-TRIF pathways. NEW & NOTEWORTHY Angiotensin II (ANG II)-induced hypertension is dependent on the endosomal Toll-like receptor 3 (TLR3)-Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF) pathway of the innate immune system but not on cell membrane localized TLR4. However, ANG II-induced cardiac hypertrophy is regulated by both TLR4-TRIF and TLR3-TRIF pathways. Thus, ANG II-induced rise in systolic blood pressure is independent of TLR4-TRIF effect on cardiac hypertrophy. The TLR3-TRIF pathway may be a potential target of therapeutic intervention.

Abstract 394: Angiotensin II Mediated Increase in Hypertension and Cardiac Hypertrophy in MyD88 Knockout Mice

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Madhu V Singh ◽  
Sailesh C Harwani ◽  
Carol A Whiteis ◽  
Michael Z Cicha ◽  
Mark W Chapleau ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Pressor Response ◽  
Marker Gene ◽  
Innate Immune ◽  
Heart Weight ◽  
Tnf Alpha ◽  
Adapter Protein ◽  
Gene Expression Analyses

Toll-like receptors (TLR) are a class of pattern-recognizing receptors (PRR) that play a central role in the innate immune response during infection and sterile injury. MyD88 is an adapter protein that mediates the majority of TLR responses. Since inflammation is a coexisting condition in several cardiovascular diseases, TLRs are thought to play a major role in these conditions. We have previously shown that indeed post-MI survival was significantly improved and cardiac fibrosis and hypertrophy were reduced in MyD88-/- mice (Singh et al. 2012. JMCC). In this study we tested whether angiotensin II (AngII) hypertension and cardiac hypertrophy depended on TLR signaling pathways mediated by MyD88. Male MyD88-/- mice and C57BL/6 mice of 10 to 12 weeks of age were subcutaneously implanted with osmotic minipumps (Alzet) eluting saline or AngII (Sigma, 733 ng/kg/min). Tailcuff pressures were measured with BP2000 (Visitech Systems). Mice were sacrificed after 3 weeks of AngII infusion and hearts were collected for weighing and gene expression analyses. In control WT mice, mean arterial pressure (MAP) remained near baseline levels during the first week of infusion averaging 71± 2 mm Hg and then increased to an average of 100 ± 3 mm Hg and 102 ± 2 mm Hg during the 2nd and 3rd weeks of infusions, respectively. In MyD88-/- mice, MAP increased from a baseline of 84 ± 3 to a high of 120 ± 7 mm Hg during the first week and then declined to 109 ± 6 and 91 ± 9 mm Hg during the 2nd and 3rd weeks. The heart weight to body weight ratios (HW/BW x 1000) after 3 weeks of AngII infusion were not significantly different between WT (5.23 ± 0.15) and MyD88-/- (4.76 ± 0.16). Increases in cardiac hypertrophic marker gene Acta1 were up 4-fold in both WT and MyD88-/- mice, and increases in proinflammatory TNF-alpha, IL-1β, and Nox4 were seen in both genotypes, but the increase in TNF-alpha was significantly greater in MyD88-/- mice. We conclude that unlike post- MI cardiac hypertrophy, the AngII cardiac hypertrophy is not MyD88 -dependent, yet the delayed Ang II pressor response is abrogated in the absence of MyD88. The delayed pressor response to AngII infusion is likely dependent on the immune system.

Comparison of fast and slow pressor effects of angiotensin II in the conscious rat

1981 ◽  
Vol 241 (3) ◽  
pp. H381-H388 ◽  
Author(s):  
A. J. Brown ◽  
J. Casals-Stenzel ◽  
S. Gofford ◽  
A. F. Lever ◽  
J. J. Morton
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Pressor Response ◽  
Control Period ◽  
Urinary Sodium Excretion ◽  
Sodium Balance ◽  
Pressor Effect ◽  
Ang Ii ◽  
Conscious Rat ◽  
Female Wistar Rats

Female Wistar rats were infused intravenously with 5% dextrose for 3 days, then with angiotensin II (ANG II) in 5% dextrose at 20 ng . kg-1 . min-1 for 7 days, and finally with dextrose for 2.5 days. ANG II raised mean arterial pressure (MAP) gradually; by the 7th day it was 49.7 mmHg higher than during the dextrose control period in the same rats. Control rats were infused with dextrose for 12.5 days; MAP did not change. Plasma ANG II concentration was measured during infusion. In hypertensive rats on the 7th day of ANG II infusion, it was six times higher than in control rats infused with dextrose. Changes of blood pressure and plasma ANG II concentration were compared in further rats infused with much larger doses of ANG II. Rats receiving 270 ng . kg-1 . min-1 for 1 h had an almost maximal direct pressor response, MAP rising 45.3 mmHg and plasma ANG II rising 32-fold compared with controls. Thus, infusion of ANG II at low dose without direct pressor effect gradually raises blood pressure to a level similar to the maximum direct pressor effect produced by larger doses of ANG II. Sodium balance and food and water intakes were also measured and did not change during prolonged infusion of ANG II at 20 ng . kg-1 . min-1. Thus, the slow pressure effect of ANG II develops at a lower and more nearly physiological plasma concentration of the peptide than do the direct pressor effect and the effects on drinking, eating, and urinary sodium excretion.

Discovery of L-162,313: a nonpeptide that mimics the biological actions of angiotensin II

1995 ◽  
Vol 268 (3) ◽  
pp. R820-R823 ◽  
Author(s):  
S. D. Kivlighn ◽  
W. R. Huckle ◽  
G. J. Zingaro ◽  
R. A. Rivero ◽  
V. J. Lotti ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Receptor Agonist ◽  
Enzyme Inhibitor ◽  
Pressor Response ◽  
Ang Ii ◽  
Aortic Smooth Muscle Cell ◽  
Maximum Increase ◽  
Aortic Smooth Muscle ◽  
Biological Actions

L-162,313 (5,7-dimethyl-2-ethyl-3-[[4-[2(n- butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]- imadazo[4,5-b]pyridine) is a nonpeptide that mimics the biological actions of angiotensin II (ANG II). The intravenous administration of L-162,313 increased blood pressure in the rat. The maximum increase in mean arterial pressure (MAP) was not different from the maximum response to ANG II in the same preparation. However, the duration of the pressor response after L-162,313 greatly exceeded that of ANG II. Pretreatment with ANG II receptor antagonists, L-158,809 (AT1 selective) or saralasin, blocked the L-162,313-induced increase in MAP. Enalaprilat, an angiotensin-converting enzyme inhibitor, failed to block the MAP response to L-162,313. In vitro, L-162,313-activated phosphoinositide turnover in rat aortic smooth muscle cell cultures was also blocked by L-158,809 and losartan (DuP-753). Therefore, L-162,313 is the first reported nonpeptide ANG II receptor agonist.

Metabolic clearance of angiotensin II in pregnant and nonpregnant sheep

1985 ◽  
Vol 249 (1) ◽  
pp. E49-E55 ◽  
Author(s):  
R. P. Naden ◽  
S. Coultrup ◽  
B. S. Arant ◽  
C. R. Rosenfeld
Keyword(s):  
Angiotensin Ii ◽  
Pressor Response ◽  
Plasma Concentrations ◽  
Metabolic Clearance ◽  
Ang Ii ◽  
Pressor Responses ◽  
Pregnant Sheep ◽  
Vascular Responsiveness ◽  
Arterial Plasma ◽  
In Pregnancy

Reduced vascular responsiveness to infused angiotensin II (ANG II) has been observed during pregnancy. It has been proposed that infusions produce lower circulating concentrations of ANG II in pregnancy, due to an increase in the metabolic clearance rate of ANG II (MCRangii). We have evaluated the MCRangii and the arterial plasma concentrations of ANG II during constant infusions of 1.15 micrograms ANG II/min into chronically instrumented pregnant (n = 6) and nonpregnant (n = 9) sheep. Although the pressor responses were significantly less in the pregnant than in the nonpregnant sheep (17.5 +/- 0.5 vs. 34.9 +/- 3.2 mmHg, P less than 0.001), the values for MCRangii were not different: 56.2 +/- 6.3 ml X min-1 X kg-1 in nonpregnant and 55.9 +/- 4.3 ml X min-1 X kg-1 in pregnant sheep. The steady-state plasma ANG II concentrations during the infusions were slightly less in pregnant than in nonpregnant sheep (388 +/- 36 vs. 454 +/- 36 pg/ml); however, this difference would be responsible for only a 2-mmHg reduction in the pressor response. We conclude that the reduced pressor response to infused ANG II in pregnancy is not due to an increase in MCRangii nor to lower plasma ANG II concentrations.

Abstract 478: FGF23 Expression in Cardiac Fibroblasts Is Augmented by S100/Calgranulins-Mediated Inflammation and Associated With Cardiac Hypertrophy, but Not in Angiotensin II-Induced Cardiac Hypertrophy

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Marion Hofmann Bowman ◽  
Brandon Gardner ◽  
Judy Earley ◽  
Debra L Rateri ◽  
Alan Daugherty ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibroblasts ◽  
Left Ventricular ◽  
Heart Weight ◽  
Ang Ii ◽  
Wild Type ◽  
Wild Type Littermate ◽  
Transgenic Expression ◽  
Significant Difference

Background: Serum S100A12 and fibroblast growth factor (FGF) 23 are biomarkers for cardiovascular mortality in patients with chronic kidney disease (CKD) and are associated with left ventricular hypertrophy (LVH). FGF23 is induced in cultured cardiac fibroblasts in response to cytokines including IL-6, TNF-a, LPS and S100/calgranulins. Moreover, hBAC-S100 transgenic mice with CKD had increased FGF23 in valvular interstitial cells and exhibited LVH. The present study was designed to examine cardiac FGF23 expression in other murine models of LVH in the absence of CKD. Methods: Hearts from five groups of male mice were studied: (i) C57BL6/J with transgenic expression a bacterial artificial chromosome of the human S100/calgranulins (S1008/9 and S100A12, hBAC-S100), (ii) wild type littermates, (iii) LDLR-/- infused with saline (29 days, 0.9%), (iv) LDLR-/- infused with angiotensin (Ang) II (29 days, 1000 ng/kg/min), and (v) fibroblast specific depletion of angiotensin II type 1a receptor (AT1aR) (S100A4-Cre x AT1aR-/- x LDLR-/-) infused with AngII. Results: hBAC-S100, but not wild type littermate mice, developed significant LVH at 10 months by heart weight/body weight (5.9 ±1.1 mg/g vs. 4.2 ±0.8, p<0.04), decreased E/A ratio, and increased LVPW thickness, and associated with increased expression of FGF23 mRNA and protein in cardiac tissue lysates (2-4 fold increase). Similarly, Ang II induced significant LVH compared to saline infused LDLR-/- mice (6.1±1.3 vs. 3.6 ±0.9 mg/g, p<0.01), and associated with increased mRNA for hypertrophic genes (ANP, BNP, b-MHC, CTGF and Col1a1). However, there was no significant difference in FGF23 mRNA and protein between Ang II and saline infused mice. Cardiac hypertrophy was attenuated in AngII-infused mice with deficiency of AT1aR (S100A4-Cre+/-xAT1aRxLDLR-/-). In vitro, Ang II (100nM) did not induce FGF23 in valvular interstitial fibroblasts or myocytes. Summary: Transgenic expression of S100/calgranulins is sufficient to induce LVH in aged mice with normal renal function, and this is associated with FGF23 expression in cardiac interstitial fibroblasts. Future studies are needed to determine whether cardiac FGF23 promotes LVH in a paracrine manner. However, FGF23 does not play a role in Ang II-induced LVH.

Abstract 152: Mitochondrial Fission Inhibitor Mdivi-1 Attenuates Angiotensin II-Induced Cardiovascular Remodeling

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Steven J Forrester ◽  
Tatsuo Kawai ◽  
Katherine J Elliott ◽  
Kunie Eguchi ◽  
Victor Rizzo ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Er Stress ◽  
Mitochondrial Fission ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Cardiovascular Remodeling ◽  
Target Organs ◽  
Quantity Control ◽  
Affect Heart Rate

Mitochondrial dysfunction has been implicated in various types of cardiovascular diseases which may involve overload and de-compensation in mitochondrial quality/quantity control. However, limited mechanistic insight is available regarding the contribution and mechanism of mitochondrial quality control in hypertension. In the present study, we tested our hypothesis that enhancement of mitochondrial fission in vascular cells is involved in hypertensive vascular remodeling. 8 week old male C57/Bl6 mice were infused with angiotensin II (1000 ng/kg/min) for 2 weeks with or without treatment of mitochondrial fission inhibitor Mdivi-1 (25 mg/kg ip every other day). Mdivi-1 significantly inhibited AngII-induced left ventricular hypertrophy assessed by heart weight body weight ratio as well as by echocardiogram. Histological assessment of the Mdivi-1-treated mouse hearts further demonstrated significant suppression of vessel hypertrophy and fibrosis induced by AngII. However, Mdivi-1 did not affect heart rate or hypertension induced by AngII assessed by telemetry. KDEL and VCAM1 staining of the heart and aorta suggest attenuation of vascular ER stress and inflammation, respectively. In cultured rat vascular smooth muscle cell (VSMCs), AngII induced mitochondrial fission promoting Drp1 phosphorylation at Ser616 and Ser637. Pretreatment of Mdivi-1 (5 microM 30 min) attenuated 100 nM AngII-induced mitochondrial fission in VSMCs assessed by mito-tracker staining. Mdivi-1 also attenuated extracellular collagen accumulation induced by AngII in VSMCs assessed by Sirius Red staining quantification kit. In conclusion, this data suggests that Mdivi-1 treatment prevents AngII-induced cardiovascular remodeling independently of hypertension via suppression of mitochondrial fission and attenuation of ER stress and inflammation in target organs.

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