IL-6 induces PI 3-kinase and nitric oxide-dependent protection and preserves mitochondrial function in cardiomyocytes

Smart, Nicola; Mojet, MH; Latchman, David S.; Marber, Michael; Duchen, Michael R.; Heads, Richard J.

doi:10.1016/j.cardiores.2005.08.017

Cited by 119 publications

(89 citation statements)

References 37 publications

(32 reference statements)

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“…In particular, protection against palmitate-induced apoptosis in clonal ␤-cells provided by unsaturated FA application was PI 3-kinase-dependent (73). In cardiomyocytes, oxidative stress-induced apoptosis was prevented by insulin in a PI 3-kinase/Akt-dependent manner (105), and the cytoprotective effect of PI 3-kinase signaling in this cell type involved enhancement of the mitochondrial ability to accumulate Ca 2ϩ without undergoing terminal depolarization (106). Our data indicate that this pathway also controls the limited opening of the mitochondrial pore, in addition to the full-size form of MPT.…”

Section: Discussionmentioning

confidence: 97%

Limited Mitochondrial Permeabilization Is an Early Manifestation of Palmitate-induced Lipotoxicity in Pancreatic β-Cells

Koshkin

Dai

Doucette

et al. 2008

Journal of Biological Chemistry

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Involvement of the mitochondrial permeability transition (MPT) pore in early stages of lipotoxic stress in the pancreatic ␤-cell lines MIN6 and INS-1 was the focus of this study. Both long term (indirect) and acute (direct) effects of fatty acid (FA) application on ␤-cell susceptibility to Ca 2؉ -induced MPT induction were examined using both permeabilized and intact ␤-cells. Long term exposure to moderate (i.e. below cytotoxic) levels of the saturated FA palmitate sensitized ␤-cell mitochondria to MPT induced by Ca 2؉ . Long term exposure to palmitate was significantly a more efficient inducer of MPT than the unsaturated FA oleate, although upon acute application both caused similar MPT activation. Application of antioxidants, inhibitors of the ceramide pathway, or modifiers of membrane fluidity did not protect ␤-cell mitochondria from FA exposure. However, significant protection was provided by co-application of the unsaturated FA oleate in a phosphatidylinositol 3-kinase-dependent manner. Characterization of MPT pore opening in response to moderate palmitate treatment revealed the opening of a unique form of MPT in ␤-cells as it encompassed features of both low and high conductance MPT states. Specifically, this MPT showed solute selectivity, characteristic of a low conductance MPT; however, it affected mitochondrial respiration and membrane potential in a way typical of a high conductance MPT. Activation of the full-size/high conductance form of MPT required application of high levels of FA that reduced growth and initiated apoptosis. These findings suggest that in the ␤-cell, MPTs can act as both initiators of cell death and as versatile modulators of cell metabolism, depending on the mode of the MPT pore induced. Mitochondrial permeability transition (MPT)2 is the calcium (Ca 2ϩ )-dependent opening of a nonspecific pore in the mitochondrial inner membrane in response to a variety of inducers and co-inducers, including inorganic phosphate (P i ), thiol oxidants, fatty acids (FA), and others. Opening of the "full-size" or "high conductance" MPT causes equilibration across the inner membrane of ions and all solutes up to 1.5 kDa, which induces mitochondrial swelling and the release of mitochondrial proteins capable of apoptosis activation (1-5). MPT can also operate in a more "limited size" or "low conductance" mode, which allows passage of only small ions across the inner mitochondrial membrane (6, 7). Because opening of the low conductance MPT does not allow passage of large molecules, but does allow the passage of small ions, mitochondrial ion gradients and energy production are affected. As such, it is thought that the low conductance MPT functions not to induce cell death but to aid in the fine regulation of cell metabolism (6). Extensive evidence documents the high conductance MPT as a cause of generalized mitochondrial dysfunction and cell death, and an important mechanism in disease pathologies such as hepatotoxicity (8), cardiac ischemia/reperfusion (9, 10), and neuronal injury (10, 11). In contrast,...

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Section: Discussionmentioning

confidence: 97%

Limited Mitochondrial Permeabilization Is an Early Manifestation of Palmitate-induced Lipotoxicity in Pancreatic β-Cells

Koshkin

Dai

Doucette

et al. 2008

Journal of Biological Chemistry

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“…Previous studies have demonstrated that IL-6 is upregulated during chronic hypertension and that constitutive IL-6/sIL-6R␣ stimulation can cause hypertrophy of the heart, as well as a reduction in infarct size in the mouse (3,8,26,35,37). Ischemia preconditioning studies have demonstrated that IL-6 can regulate the expression of cardioprotective factors such as inducible nitric oxide synthase and cyclooxygenase-2 (14,43). These data have led to speculation from several groups, including our own, that IL-6 can be cardioprotective; therefore, we hypothesized that an IL-6 loss would be deleterious to the heart (32).…”

Section: Discussionmentioning

confidence: 99%

“…IL-6 is a pleiotropic cytokine that regulates numerous biological functions in a cell-specific manner in various organs, including the heart (28). The IL-6 family of cytokines includes IL-6, IL-11, IL-27, leukemia-inhibitory factor-1, oncostatin-M, ciliary neurotrophic factor, and cardiotrophin-1 (1,10,14,28,43,45). The biological activity of IL-6 is regulated by binding to the IL-6R␣/gp130 signal transduction complex (28).…”

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confidence: 99%

IL-6 loss causes ventricular dysfunction, fibrosis, reduced capillary density, and dramatically alters the cell populations of the developing and adult heart

Banerjee¹,

Fuseler²,

Intwala³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

106

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Interleukin-6 (IL-6) is a pleiotropic cytokine responsible for many different processes including the regulation of cell growth, apoptosis, differentiation, and survival in various cell types and organs, including the heart. Recent studies have indicated that IL-6 is a critical component in the cell-cell communication between myocytes and cardiac fibroblasts. In this study, we examined the effects of IL-6 deficiency on the cardiac cell populations, cardiac function, and interactions between the cells of the heart, specifically cardiac fibroblasts and myocytes. To examine the effects of IL-6 loss on cardiac function, we used the IL-6 −/− mouse. IL-6 deficiency caused severe cardiac dilatation, increased accumulation of interstitial collagen, and altered expression of the adhesion protein periostin. In addition, flow cytometric analyses demonstrated dramatic alterations in the cardiac cell populations of IL-6 −/− mice compared with wild-type littermates. We observed a marked increase in the cardiac fibroblast population in IL-6 −/− mice, whereas a concomitant decrease was observed in the other cardiac cell populations examined. Moreover, we observed increased cell proliferation and apoptosis in the developing IL-6 −/− heart. Additionally, we observed a significant decrease in the capillary density of IL-6 −/− hearts. To elucidate the role of IL-6 in the interactions between cardiac fibroblasts and myocytes, we performed in vitro studies and demonstrated that IL-6 deficiency attenuated the activation of the STAT3 pathway and VEGF production. Taken together, these data demonstrate that a loss of IL-6 causes cardiac dysfunction by shifting the cardiac cell populations, altering the extracellular matrix, and disrupting critical cell-cell interactions.

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“…The fact that the classic proinflammatory cytokines, tumor necrosis factor-␣ and IL-1␤, do not increase with exercise indicates that the IL-6 cytokine cascade induced by exercise, and perhaps by ␣ 1A -ARs, markedly differs from the cytokine cascade induced by infections. For instance, IL-6 can induce a phosphatidylinositol-3-kinase and NO-dependent protection of cardiomyocytes (Smart et al, 2006). It seems that only CAM ␣ 1A -AR mice, which show cardioprotective phenotypes (Huang et al, 2007), have increased serum IL-6 levels.…”

Section: Discussionmentioning

confidence: 99%

α₁-Adrenergic Receptor Stimulates Interleukin-6 Expression and Secretion through Both mRNA Stability and Transcriptional Regulation: Involvement of p38 Mitogen-Activated Protein Kinase and Nuclear Factor-κB

Perez¹,

Papay²,

Shi³

2009

Mol Pharmacol

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Our previous studies have demonstrated that activation of ␣ 1 -adrenergic receptors (ARs) increased interleukin-6 (IL-6) mRNA expression and protein secretion, which is probably an important yet unknown mechanism contributing to the regulation of cardiac function. Using Rat-1 fibroblasts stably transfected with the ␣ 1A -AR subtype and primary mouse neonatal cardiomyocytes, we elucidated the basic molecular mechanisms responsible for the ␣ 1 -AR modulation of IL-6 expression. IL-6 mRNA production mediated by ␣ 1 -AR peaked at 1 to 2 h. Studies of the mRNA decay rate indicated that ␣ 1 -AR activation enhanced IL-6 mRNA stability. Analysis of IL-6 promoter activity using a series of deletion constructs indicated that ␣ 1 -ARs enhanced IL-6 transcription through several transcriptional elements, including nuclear factor B (NF-B). Inhibition of ␣ 1 -AR mediated IL-6 production and secretion by actinomycin D and the increase of intracellular IL-6 levels by ␣ 1 -AR activation suggest that ␣ 1 -AR mediated IL-6 secretion through de novo synthesis. Both IL-6 transcription and protein secretion mediated by ␣ 1 -ARs were significantly reduced by chemical inhibitors for p38 mitogen-activated protein kinase (MAPK) and NF-B and by a dominant-negative construct of p38 MAPK. Serum level of IL-6 was elevated in transgenic mice expressing a constitutively active mutant of the ␣ 1A -AR subtype but not in a similar mouse model expressing the ␣ 1B -AR subtype. Our results indicate that ␣ 1 -ARs stimulated IL-6 expression and secretion through regulating both mRNA transcription and stability, involving p38 MAPK and NF-B pathways.

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IL-6 induces PI 3-kinase and nitric oxide-dependent protection and preserves mitochondrial function in cardiomyocytes

Cited by 119 publications

References 37 publications

Limited Mitochondrial Permeabilization Is an Early Manifestation of Palmitate-induced Lipotoxicity in Pancreatic β-Cells

Limited Mitochondrial Permeabilization Is an Early Manifestation of Palmitate-induced Lipotoxicity in Pancreatic β-Cells

IL-6 loss causes ventricular dysfunction, fibrosis, reduced capillary density, and dramatically alters the cell populations of the developing and adult heart

α₁-Adrenergic Receptor Stimulates Interleukin-6 Expression and Secretion through Both mRNA Stability and Transcriptional Regulation: Involvement of p38 Mitogen-Activated Protein Kinase and Nuclear Factor-κB

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IL-6 induces PI 3-kinase and nitric oxide-dependent protection and preserves mitochondrial function in cardiomyocytes

Cited by 119 publications

References 37 publications

Limited Mitochondrial Permeabilization Is an Early Manifestation of Palmitate-induced Lipotoxicity in Pancreatic β-Cells

Limited Mitochondrial Permeabilization Is an Early Manifestation of Palmitate-induced Lipotoxicity in Pancreatic β-Cells

IL-6 loss causes ventricular dysfunction, fibrosis, reduced capillary density, and dramatically alters the cell populations of the developing and adult heart

α1-Adrenergic Receptor Stimulates Interleukin-6 Expression and Secretion through Both mRNA Stability and Transcriptional Regulation: Involvement of p38 Mitogen-Activated Protein Kinase and Nuclear Factor-κB

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Resources

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α₁-Adrenergic Receptor Stimulates Interleukin-6 Expression and Secretion through Both mRNA Stability and Transcriptional Regulation: Involvement of p38 Mitogen-Activated Protein Kinase and Nuclear Factor-κB