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 Elevated myocardial Na+/H+ exchanger isoform 1 activity elicits gene expression that leads to cardiac hypertrophy

2010 ◽  
Vol 42 (3) ◽  
pp. 374-383 ◽  
Author(s):  
Jin Xue ◽  
Fatima Mraiche ◽  
Dan Zhou ◽  
Morris Karmazyn ◽  
Tatsujiro Oka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Interstitial Fibrosis ◽  
Gene Activation ◽  
Weight Ratio ◽  
Heart Weight ◽  
Peroxisome Proliferator ◽  
Cross Sectional

In myocardial disease, elevated expression and activity of Na+/H+ exchanger isoform 1 (NHE1) are detrimental. To better understand the involvement of NHE1, transgenic mice with elevated heart-specific NHE1 expression were studied. N-line mice expressed wild-type NHE1, and K-line mice expressed activated NHE1. Cardiac morphology, interstitial fibrosis, and cardiac function were examined by histological staining and echocardiography. Differences in gene expression between the N-line or K-line and nontransgenic littermates were probed with genechip analysis. We found that NHE1 K-line (but not N-line) hearts developed hypertrophy, including elevated heart weight-to-body weight ratio and increased cross-sectional area of the cardiomyocytes, interstitial fibrosis, as well as depressed cardiac function. N-line hearts had modest changes in gene expression (50 upregulations and 99 downregulations, P < 0.05), whereas K-line hearts had a very strong transcriptional response (640 upregulations and 677 downregulations, P < 0.05). In addition, the magnitude of expression alterations was much higher in K-line than N-line mice. The most significant changes in gene expression were involved in cardiac hypertrophy, cardiac necrosis/cell death, and cardiac infarction. Secreted phosphoprotein 1 and its signaling pathways were upregulated while peroxisome proliferator-activated receptor γ signaling was downregulated in K-line mice. Our study shows that expression of activated NHE1 elicits specific pathways of gene activation in the myocardium that lead to cardiac hypertrophy, cell death, and infarction.

scholarly journals Polydatin prevents angiotensin II-induced cardiac hypertrophy and myocardial superoxide generation

2014 ◽  
Vol 240 (10) ◽  
pp. 1352-1361 ◽  
Author(s):  
Qi Zhang ◽  
Yingying Tan ◽  
Nan Zhang ◽  
Fanrong Yao
Keyword(s):  
Nadph Oxidase ◽  
Cardiac Hypertrophy ◽  
Oxidase Activity ◽  
Weight Ratio ◽  
Heart Weight ◽  
Leucine Incorporation ◽  
Dependent Manner ◽  
Ang Ii ◽  
Nadph Oxidase Activity ◽  
Cultured Cardiomyocytes

Our studies and others recently demonstrate that polydatin, a resveratrol glucoside, has antioxidative and cardioprotective effects. This study aims to investigate the direct effects of polydatin on Ang II-induced cardiac hypertrophy to explore the potential role of polydatin in cardioprotection. Our results showed that in primary cultured cardiomyocytes, polydatin blocked Ang II-induced cardiac hypertrophy in a dose-dependent manner, which were associated with reduction in the cell surface area and [3H]leucine incorporation, as well as attenuation of the mRNA expressions of atrial natriuretic factor and β-myosin heavy chain. Furthermore, polydatin prevented rat cardiac hypertrophy induced by Ang II infusion, as assessed by heart weight-to-body weight ratio, cross-sectional area of cardiomyocyte, and gene expression of hypertrophic markers. Further investigation demonstrated that polydatin attenuated the Ang II-induced increase in the reactive oxygen species levels and NADPH oxidase activity in vivo and in vitro. Polydatin also blocked the Ang II-stimulated increases of Nox4 and Nox2 expression in cultured cardiomyocytes and the hearts of Ang II-infused rats. Our results indicate that polydatin has the potential to protect against Ang II-mediated cardiac hypertrophy through suppression of NADPH oxidase activity and superoxide production. These observations may shed new light on the understanding of the cardioprotective effect of polydatin.

scholarly journals Modulation of Macrophage Infiltration and Inflammatory Activity by the Phosphatase SHP-1 in Virus-Induced Demyelinating Disease

2008 ◽  
Vol 83 (2) ◽  
pp. 522-539 ◽  
Author(s):  
George P. Christophi ◽  
Chad A. Hudson ◽  
Michael Panos ◽  
Ross C. Gruber ◽  
Paul T. Massa
Keyword(s):  
Gene Expression ◽  
Demyelinating Disease ◽  
Tyrosine Phosphatase ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Wild Type ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
High Level ◽  
Deficient Mice

ABSTRACT The protein tyrosine phosphatase SHP-1 is a crucial negative regulator of cytokine signaling and inflammatory gene expression, both in the immune system and in the central nervous system (CNS). Mice genetically lacking SHP-1 (me/me) display severe inflammatory demyelinating disease following inoculation with the Theiler's murine encephalomyelitis virus (TMEV) compared to infected wild-type mice. Therefore, it became essential to investigate the mechanisms of TMEV-induced inflammation in the CNS of SHP-1-deficient mice. Herein, we show that the expression of several genes relevant to inflammatory demyelination in the CNS of infected me/me mice is elevated compared to that in wild-type mice. Furthermore, SHP-1 deficiency led to an abundant and exclusive increase in the infiltration of high-level-CD45-expressing (CD45hi) CD11b+ Ly-6Chi macrophages into the CNS of me/me mice, in concert with the development of paralysis. Histological analyses of spinal cords revealed the localization of these macrophages to extensive inflammatory demyelinating lesions in infected SHP-1-deficient mice. Sorted populations of CNS-infiltrating macrophages from infected me/me mice showed increased amounts of viral RNA and an enhanced inflammatory profile compared to wild-type macrophages. Importantly, the application of clodronate liposomes effectively depleted splenic and CNS-infiltrating macrophages and significantly delayed the onset of TMEV-induced paralysis. Furthermore, macrophage depletion resulted in lower viral loads and lower levels of inflammatory gene expression and demyelination in the spinal cords of me/me mice. Finally, me/me macrophages were more responsive than wild-type macrophages to chemoattractive stimuli secreted by me/me glial cells, indicating a mechanism for the increased numbers of infiltrating macrophages seen in the CNS of me/me mice. Taken together, these findings demonstrate that infiltrating macrophages in SHP-1-deficient mice play a crucial role in promoting viral replication by providing abundant viral targets and contribute to increased proinflammatory gene expression relevant to the effector mechanisms of macrophage-mediated demyelination.

Abstract 559: Diacylglycerol Kinase-ζ Rescues Gαq-induced Heart Failure

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Takeshi Niizeki ◽  
Yasuchika Takeishi ◽  
Yo Koyama ◽  
Tatsuro Kitahara ◽  
Satoshi Suzuki ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Critical Role ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Negative Regulator ◽  
Heart Weight ◽  
Type I ◽  
Gpcr Signaling

Background: It has been reported that the expression of a constitutively active mutant of the G protein αq subunit in the hearts of transgenic mice (Gαq-TG) induces cardiac hypertrophy and lethal heart failure. Thus, the Gαq protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG) and protein kinase C (PKC), plays a critical role in the development of cardiac hypertrophy and heart failure. DAG kinase (DGK) catalyzes DAG and controls cellular DAG levels, and thus may act as a negative regulator of GPCR signaling. In this study, we tested the hypothesis that DGKζ rescues Gαq-TG mice from developing heart failure. Methods and Results: We generated double transgenic mice (Gαq/DGKζ-TG) with cardiac-specific overexpression of both DGKζ and constitutive active Gαq by crossing Gαq-TG mice with transgenic mice with cardiac-specific overexpression of DGKζ (DGKζ-TG), and the pathophysiological consequences were analyzed. DGKζ inhibited cardiac hypertrophy and progression to heart failure in Gαq-TG mice (Table ). DGKζ prevented dilatation of left ventricular dimension and reduction of left ventricular fractional shortening in Gαq-TG mice. Markedly increased left ventricular end-diastolic pressure in Gαq-TG mice was normalized in Gαq/DGKζ-TG mice. Increases in heart weight/body weight ratio and cardiomyocyte cross sectional area were attenuated in Gαq/DGKζ-TG mice. Translocation of PKC α and ε isoforms, activation of JNK and p38 MAPK induced by Gαq were attenuated by DGKζ. DGKζ reduced fibrotic changes and concomitant upregulation of fibrosis-related genes such as collagen type I and type III induced by Gαq. DGKζ improved the survival rate of Gαq-TG mice. Conclusions: These results demonstrate the first evidence that DGKζ prevents cardiac dysfunction and heart failure by activated Gαq without detectable adverse effects in in vivo hearts and suggest that DGKζ represents a novel therapeutic target for cardiac hypertrophy and heart failure. Summary of the results

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.

scholarly journals Chronic C-Type Natriuretic Peptide Infusion Attenuates Angiotensin II-Induced Myocardial Superoxide Production and Cardiac Remodeling

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Yasuhiro Izumiya ◽  
Satoshi Araki ◽  
Hiroki Usuku ◽  
Taku Rokutanda ◽  
Shinsuke Hanatani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
Superoxide Production ◽  
Heart Weight ◽  
Ang Ii ◽  
Myocardial Oxidative Stress

Myocardial oxidative stress and inflammation are key mechanisms in cardiovascular remodeling. C-type natriuretic peptide (CNP) is an endothelium-derived cardioprotective factor, although its effect on cardiac superoxide generation has not been investigated in vivo. This study tested the hypothesis that suppression of superoxide production contributes to the cardioprotective action of CNP. Angiotensin II (Ang II) or saline was continuously infused subcutaneously into mice using an osmotic minipump. Simultaneously with the initiation of Ang II treatment, mice were infused with CNP (0.05 μg/kg/min) or vehicle for 2 weeks. The heart weight to tibial length ratio was significantly increased by Ang II in vehicle-treated mice. Treatment with CNP decreased Ang II-induced cardiac hypertrophy without affecting systolic blood pressure. Echocardiography showed that CNP attenuated Ang II-induced increase in wall thickness, left ventricular dilatation, and decrease in fractional shortening. CNP reduced Ang II-induced increases in cardiomyocyte size and interstitial fibrosis and suppressed hypertrophic- and fibrosis-related gene expression. Finally, CNP decreased Ang II-induced cardiac superoxide production. These changes were accompanied by suppression of NOX4 gene expression. Our data indicate that treatment with CNP attenuated Ang II-induced cardiac hypertrophy, fibrosis, and contractile dysfunction which were accompanied by reduced cardiac superoxide production.

Sign in / Sign up

Export Citation Format

Share Document