Loss of a gp130 Cardiac Muscle Cell Survival Pathway Is a Critical Event in the Onset of Heart Failure during Biomechanical Stress

Hirota, Hisao; Chen, Ju; Betz, Ulrich; Rajewsky, Klaus; Gu, Yusu; Ross, John; Müller, Werner; Chien, Kenneth R.

doi:10.1016/s0092-8674(00)80729-1

Cited by 624 publications

(407 citation statements)

References 55 publications

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“…In contrast to controls, the cardiac ventricle-gp130 knockouts could not sustain the compensated state; instead, they quickly developed cardiac dilatation and failure because of massive cardiac myocyte apoptosis. 19 In this study, the IL-6 Ϫ/Ϫ mice were also unable to sustain the compensatory hepatic hyperplasia associated with the biomechanical stress of BDL. However, failure to maintain the compensated state was due to lower hepatocyte proliferation and not an increased rate of apoptosis.…”

Section: Discussionmentioning

confidence: 62%

“…Instability of the compensated state in the IL-6 Ϫ/Ϫ mice after BDL is similar to a recent report of cardiac ventricle-restricted knockout of gp130 via CreloxP-mediated recombination. 19 Aortic banding in these mice created a pressure overload, or biomechanical stress within the heart, which results in adaptive ventricular hypertrophy. In contrast to controls, the cardiac ventricle-gp130 knockouts could not sustain the compensated state; instead, they quickly developed cardiac dilatation and failure because of massive cardiac myocyte apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…18 In addition, recent studies have shown that gp130 signaling is critical to the maintenance of cardiac myocyte mass during hypertrophic compensation for the biomechanical stress of aortic banding. 19 Obstructive cholangiopathy is associated with biomechanical stress of the biliary tree and an increased expression of the IL-6/gp80/gp130 receptor-ligand signaling system. 20,21 We therefore tested the hypothesis that the absence of IL-6 would lead to phenotypic alterations in the response to long-term bile duct ligation (BDL).…”

mentioning

confidence: 99%

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The Development and Compensation of Biliary Cirrhosis in Interleukin-6-Deficient Mice

Ezure

Sakamoto

Tsuji

et al. 2000

The American Journal of Pathology

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In an effort to understand the role of IL-6/gp130 signaling in chronic liver injury, IL-6 deficient (IL-6 ؊/؊ ) and wild-type control (IL-6 ؉/؉ ) mice were subjected to bile duct ligation (BDL) for 12 weeks. This maneuver causes chronic biomechanical stress and liver injury, fueling sustained biliary epithelial and hepatocyte proliferation. By 12 weeks after BDL, IL-6 ؊/؊ mice develop significantly higher total serum bilirubin levels (23.2 ؎ 2.3 versus 14.9 ؎ 2.1 mg/dl, P < 0.0001; delta bilirubin subfraction 16.7 ؎ 4.0% versus 9.2 ؎ 1.8%; P < 0.002), and the majority (15/18) show "black" gallbladder bile, compared to IL-6 ؉/؉ mice (5/16; P < 0.003). The IL-6 ؊/؊ mice also cannot sustain the compensatory liver mass increase commonly seen with chronic obstructive cholangiopathy, because of less hepatocyte proliferation, despite a rate of hepatocyte apoptosis similar to that of IL-6 ؉/؉ mice. Moreover, IL-6 ؊/؊ mice show a more advanced stage of biliary fibrosis and a higher mortality rate than the IL-6 ؉/؉ controls (51% versus 23%; P < 0.02). These phenotypic changes in the IL-6 ؊/؊ mice are associated with decreased expression and phosphorylation of gp130 and the transcription factor STAT3, compared to IL-6 ؉/؉ mice. Daily treatment with exogenous recombinant IL-6 for 3-6 weeks starting at 6 weeks after BDL significantly lowers the serum total bilirubin in both groups. In the IL-6 ؊/؊ mice, exogenous IL-6 treatment also increases the level of gp130 protein expression and completely reverses the loss of liver mass by increasing the hepatocyte proliferation. In conclusion, IL-6 appears to contribute to biliary tree integrity and maintenance of hepatocyte mass during chronic injury. Interleukin-6 (IL-6)/gp-130 signaling is involved acutely in hepatocyte 1,2 and biliary epithelial cell (BEC) growth control and pathobiology. For example, liver regeneration after partial hepatectomy (PH) is delayed in IL-6 Ϫ/Ϫ mice, 1,2 whereas IL-6/sIL-6R double transgenic mice develop hepatocellular hyperplasia and adenomas. 3 Although data on the in vitro effects of IL-6 on hepatocyte proliferation are conflicting, 4,5 there are at least two mechanisms by which IL-6/gp-130 promotes BEC growth in vitro. IL-6 is able to directly stimulate BEC DNA synthesis 6 and inhibit apoptosis, via an increase of the bcl-2/ bax ratio. 7 When stimulated by other proinflammatory cytokines or phorbol esters, nonneoplastic BEC can also produce and secrete IL-6, which can then act as an autocrine growth factor under conditions of BEC stress. 6,8,9 Serum and liver IL-6 levels are also elevated in patients with chronic inflammatory liver diseases. 10 -13 In this setting, IL-6 has traditionally been considered to exert a profibrogenic and mitoinhibitory influence on the development of cirrhosis. 10,14 -17 However, in other "chronic inflammatory proliferative disorders," such as psoriasis and rheumatoid arthritis, IL-6 has been linked with keratinocyte and synovial cell proliferation, respectively. 18 In addition, recent studies have shown that gp130 sign...

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Development and Compensation of Biliary Cirrhosis in Interleukin-6-Deficient Mice

Ezure

Sakamoto

Tsuji

et al. 2000

The American Journal of Pathology

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“…In the MESA‐RV cohort, higher levels of IL‐6 and CRP have been shown to be associated with lower RV mass and smaller RV volumes 34. IL‐6, and its signaling pathways through glycoprotein 130, mediate the interface between the cardiomyocyte's compensatory remodeling and apoptosis in response to injury, which could explain the reduction in RV size 52, 53. Collectively, these findings imply that systemic arterial health could affect the RV through vasoactive mediators by a direct effect through the coronary flow and microvasculature.…”

Section: Discussionmentioning

confidence: 99%

Association of Systemic Arterial Properties With Right Ventricular Morphology: The Multi‐Ethnic Study of Atherosclerosis (MESA)‐Right Ventricle Study

Al‐Naamani

Chirinos

Zamani

et al. 2016

JAHA

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BackgroundSystemic arterial stiffness is recognized as a major contributor to development of left ventricular dysfunction and failure; however, the relationship of systemic arterial properties and the right ventricle (RV) is unknown.Methods and ResultsThe associations between systemic arterial measures (total arterial compliance [TAC], systemic vascular resistance [SVR], and aortic augmentation index [AI]) and RV morphology (mass, end‐systolic [RVESV] and end‐diastolic volume [RVEDV], and ejection fraction [RVEF]) were examined using data from the Multi‐Ethnic Study of Atherosclerosis. All analyses were adjusted for anthropometric, demographic, and clinical variables and the corresponding left ventricular parameter. A total of 3842 subjects without clinical cardiovascular disease were included with a mean age of 61 years, 48% male, 39% non‐Hispanic white, 25% Chinese‐American, 23% Hispanic, and 13% black. RV measures were within normal range for age and sex. A 1‐mL/mm Hg decrease in TAC was associated with 3.9‐mL smaller RVESV, 7.6‐mL smaller RVEDV, and 2.4‐g lower RV mass. A 5‐Wood‐unit increase in SVR was associated with 0.6‐mL decrease in RVESV, 1.7‐mL decrease in RVEDV, and 0.4‐g decrease in RV mass. A 1% increase in AI was associated with 0.2‐mL decrease in RVEDV. We found significant effect modification by age, sex, and race for some of these relationships, with males, whites, and younger individuals having greater decreases in RV volumes and mass.ConclusionsMarkers of increased systemic arterial load were associated with smaller RV volumes and lower RV mass in a population of adults without clinical cardiovascular disease.

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“…In animal models, the transgenic cardiac expression and conditional activation of procaspase-8 led to a significant cardiac apoptosis and a lethaldilated cardiomyopathy; both can be prevented by an administration of a broad-spectrum caspase inhibitor (157). In a mouse model of chronic pressure overload, the conditional deletion of cardiac gp-130 cytokine receptor led to the rapid onset of dilated cardiomyopathy and a massive induction of cardiomyocyte apoptosis versus that in the control mice which exhibit compensatory hypertrophy, thus suggesting that cardiomyocyte apoptosis is a critical element in the transition between compensatory cardiac hypertrophy and heart failure (52). In a rat model of I/R injury, an intravenous administration of benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a broad caspase inhibitor, resulted in a modest but significant reduction in infarct size (33.4%) and cardiomyocyte apoptosis (72.1%) (163), demonstrating a link between cardiomyocyte apoptosis and ischemic myocardial injury.…”

Section: Tlr Signaling Modulates Cardiomyocyte Apoptosismentioning

confidence: 99%

Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

Chao¹

2009

American Journal of Physiology-Heart and Circulatory Physiology

212

166

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Toll-like receptors (TLRs) represent the first line of host defense against microbial infection and play a pivotal role in both innate and adaptive immunity. TLRs recognize invading pathogens through molecular pattern recognition, transduce signals via distinct intracellular pathways involving a unique set of adaptor proteins and kinases, and ultimately lead to the activation of transcription factors and inflammatory responses. Among 10 TLRs identified in humans, at least two exist in the heart, i.e., TLR2 and TLR4. In addition to the critical role of these in mediating cardiac dysfunction in septic conditions, emerging evidence suggests that the TLRs can also recognize endogenous ligands and may play an important role in modulating cardiomyocyte survival and in ischemic myocardial injury. In animal models of ischemia-reperfusion injury or in hypoxic cardiomyocytes in vitro, the administration of a sublethal dose of lipopolysaccharide, which signals through TLR4, reduces subsequent myocardial infarction, improves cardiac functions, and attenuates cardiomyocyte apoptosis. By contrast, a systemic deficiency of TLR2, TLR4, or myeloid differentiation primary-response gene 88, an adaptor critical for all TLR signaling, except TLR3, leads to an attenuated myocardial inflammation, a smaller infarction size, a better preserved ventricular function, and a reduced ventricular remodeling after ischemic injury. These loss-of-function studies suggest that both TLRs contribute to myocardial inflammation and ischemic injury in the heart although the exact contribution of cardiac (vs. circulatory cell) TLRs remains to be defined. These recent studies demonstrate an emerging role for TLRs as a critical modulator in both cell survival and tissue injury in the heart.

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Loss of a gp130 Cardiac Muscle Cell Survival Pathway Is a Critical Event in the Onset of Heart Failure during Biomechanical Stress

Cited by 624 publications

References 55 publications

The Development and Compensation of Biliary Cirrhosis in Interleukin-6-Deficient Mice

The Development and Compensation of Biliary Cirrhosis in Interleukin-6-Deficient Mice

Association of Systemic Arterial Properties With Right Ventricular Morphology: The Multi‐Ethnic Study of Atherosclerosis (MESA)‐Right Ventricle Study

Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

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