Regulation of Cardiac Myocyte Contractile Function by Inducible Nitric Oxide Synthase (iNOS): Mechanisms of Contractile Depression by Nitric Oxide

Joe, Edwin K; Schussheim, Adam E.; Dan, Longrois; Mäki, Tiina; Kelly, Ralph A.; Smith, Thomas W.; Balligand, Jean‐Luc

doi:10.1006/jmcc.1997.0593

Cited by 94 publications

(62 citation statements)

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“…As a proinflammatory cytokine, it induces the expression of IL-1␤, tumor necrosis factor-␣, and iNOS (14,15). Both IL-1␤ and tumor necrosis factor-␣ act as negative myocardial inotropes, and induction of iNOS and iNOS-mediated nitric oxide generation play a critical role in myocardial dysfunction (57)(58)(59)(60)(61)(62). Recently, administration of IL-18 has been shown to induce myocardial contractile function in vivo and cardiomyocyte contractility in vitro (18), suggesting that IL-18 may play a role in post-ischemic myocardial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-18 Is a Pro-hypertrophic Cytokine That Acts through a Phosphatidylinositol 3-Kinase-Phosphoinositide-dependent Kinase-1-Akt-GATA4 Signaling Pathway in Cardiomyocytes

Chandrasekar

Mummidi

Claycomb

et al. 2005

Journal of Biological Chemistry

115

113

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In patients with congestive heart failure, high serum levels of the proinflammatory cytokine interleukin (IL)-18 were reported. A positive correlation was described between serum IL-18 levels and the disease severity. IL-18 has also been shown to induce atrial natriuretic factor (ANF) gene expression in adult cardiomyocytes. Because re-expression of the fetal gene ANF is mostly associated with hypertrophy, a hallmark of heart failure, we hypothesized that IL-18 induces cardiomyocyte hypertrophy. Treatment of the cardiomyocyte cell line HL-1 with IL-18 induced hypertrophy as characterized by increases in protein synthesis, phosphorylated p70 S6 kinase, and ribosomal S6 protein levels as well as cell surface area. Furthermore, IL-18 induced ANF gene transcription in a time-dependent manner as evidenced by increased ANF secretion and ANF promoter-driven reporter gene activity. Investigation into possible signal transduction pathways mediating IL-18 effects revealed that IL-18 activates phosphoinositide 3-kinase (PI3K), an effect that was blocked by wortmannin and LY-294002. IL-18 induced Akt phosphorylation and stimulated its activity, effects that were abolished by Akt inhibitor or knockdown. IL-18 stimulated GATA4 DNA binding activity and increased transcription of a reporter gene driven by multimerized GATA4-binding DNA elements. Pharmacological inhibition or knockdown studies revealed that IL-18 induced cardiomyocyte hypertrophy and ANF gene transcription via PI3K, PDK1, Akt, and GATA4. Most importantly, IL-18 induced ANF gene transcription and hypertrophy of neonatal rat ventricular myocytes via PI3K-, Akt-, and GATA4-dependent signaling. Together these data provide the first evidence that IL-18 induces cardiomyocyte hypertrophy via PI3K-dependent signaling, defines a mechanism of IL-18-mediated ANF gene transcription, and further supports a role for IL-18 in inflammatory heart diseases including heart failure.

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Section: Discussionmentioning

confidence: 99%

Interleukin-18 Is a Pro-hypertrophic Cytokine That Acts through a Phosphatidylinositol 3-Kinase-Phosphoinositide-dependent Kinase-1-Akt-GATA4 Signaling Pathway in Cardiomyocytes

Chandrasekar

Mummidi

Claycomb

et al. 2005

Journal of Biological Chemistry

115

113

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“…Finkel et al 35 showed that the depression of isolated papillary muscle contractile function caused by TNFa or IL6 was blocked when an L-arginine analogue was added as a specific inhibitor of NO synthase (NOS). Joe et al 36 demonstrated that shortening of myocytes is impaired when they are exposed to media in which macrophages are stimulated with lipopolysaccharide and that this can be blocked by inhibition of NOS.…”

Section: Discussionmentioning

confidence: 99%

“…The remaining sample was frozen immediately after biopsy at À801C and used for molecular analysis. In four pts, one heart transplanted (case 1) and three autoptic cases (cases 11,27,36), the whole heart has been also evaluated.…”

Section: Patientsmentioning

confidence: 99%

Overexpression of tumor necrosis factor (TNF)α and TNFα receptor I in human viral myocarditis: clinicopathologic correlations

et al. 2004

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Proinflammatory cytokines, including tumor necrosis factor (TNF)a, have been recognized as important physiopathogenetic factors in the initiation and continuation of inflammatory cardiomyopathies. Experimental and preliminary human studies have demonstrated that TNFa plays a crucial role in enteroviral-induced myocarditis. In this study, we investigated the expression of TNFa and both its receptors (TNFRI and TNFRII) in both viral and nonviral myocarditis. Myocardial expression of TNFa was then correlated with different clinical and pathologic findings. TNFa expression was investigated in endomyocardial biopsies obtained from 38 patients with myocarditis and from eight control subjects by using reverse transcriptase-polymerase chain reaction (PCR) and immunohistochemistry. Viral etiology was diagnosed by PCR in 20 cases: enterovirus in seven, Epstein-Barr virus in four, hepatitis C virus in three, adenovirus in two, influenza virus in two, cytomegalovirus in one, and double infection adenovirus and enterovirus in one. Immunohistochemistry was also used to analyze both TNFa receptors (RI and RII). A semiquantitative analysis was employed (score 0-3) for necrosis, inflammation, fibrosis and immunohistochemical findings. TNFa mRNA and TNFa protein were significantly more present in viral myocarditis than in nonviral myocarditis (16/20 vs 3/18, P ¼ 0.001). Remarkable immunostaining was observed for both receptors, particularly TNFRI. Histological analysis revealed that myocardial necrosis (mean score 1.89 vs 1.15, P ¼ 0.01) and cellular infiltration (mean score 2.26 vs 1.78, P ¼ 0.05) were more prominent in TNFa-positive cases. Among TNFa-positive cases, the greater TNFa mRNAs, the more impaired was cardiac function. Our findings suggest that the expression of TNFa may play an important role in the pathogenesis of viral myocarditis of any etiology and may influence the severity of cardiac dysfunction. Cytokine effects are more strictly linked to overexpression of TNFRI.

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“…Nevertheless, the induction of these molecules in cardiomyocytes could also play a detrimental role in chronic Chagas' heart disease. 1,28 Nitric oxide may directly regulate the contractile properties of muscle cells 10 and lead to depressed cardiac function 29 and myocardial damage. 30 This could further potentiate chemokine-driven inflammation and tissue damage.…”

Section: Discussionmentioning

confidence: 99%

Trypanosoma cruzi –Infected Cardiomyocytes Produce Chemokines and Cytokines That Trigger Potent Nitric Oxide–Dependent Trypanocidal Activity

Machado¹,

Martins²,

Aliberti³

et al. 2000

Circulation

225

213

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Background-The pathogenesis of myocarditis that occurs in Trypanosoma cruzi-infected mice is still poorly understood.Therefore, it is important to know the mediators that trigger leukocyte migration to the heart as well as the cellular source of these possible mediators. In this study, we investigated (1) NO synthase (NOS) induction, (2) NO synthesis, (3) trypanocidal activity, and (4) chemokine and cytokine mRNA expression by isolated cardiomyocytes infected with T cruzi. Methods and Results-Mouse cardiomyocytes were isolated, infected with T cruzi, and evaluated for induction of inducible NOS (iNOS), nitrite production, trypanocidal activity, and cytokine and chemokine mRNA expression. We found that T cruzi-infected murine embryonic cardiomyocytes produced nitrite and expressed mRNAs for the chemokines chemokine growth-related oncogene, monokine induced by interferon-␥, macrophage inflammatory protein-2, interferon-␥-inducible protein, RANTES, and monocyte chemotactic protein, for iNOS, and for the cytokines tumor necrosis factor (TNF)-␣ and interleukin (IL)-1␤. Separate addition of IL-1␤, interferon-␥, TNF-␣ or monocyte chemotactic protein, macrophage inflammatory protein-2, and interferon-␥-inducible protein, to cultured cardiomyocytes resulted in NO production but low trypanocidal activity. However, simultaneous addition of IL-1␤, interferon-␥, and TNF-␣ or the chemokines to cultures resulted in the induction of iNOS, high levels of nitrite, and a marked trypanocidal activity. The iNOS/L-arginine pathway mediated the latter activity, inasmuch as it was inhibited by treatment with N G -monomethyl-L-arginine. Conclusions-These results indicate that iNOS activation and the proinflammatory cytokines and chemokines produced by cardiomyocytes are likely to control parasite growth and cell influx, thus contributing to the pathogenesis of chagasic cardiomyopathy seen in T cruzi-infected mice. (Circulation. 2000;102:3003-3008.)

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Regulation of Cardiac Myocyte Contractile Function by Inducible Nitric Oxide Synthase (iNOS): Mechanisms of Contractile Depression by Nitric Oxide

Cited by 94 publications

References 0 publications

Interleukin-18 Is a Pro-hypertrophic Cytokine That Acts through a Phosphatidylinositol 3-Kinase-Phosphoinositide-dependent Kinase-1-Akt-GATA4 Signaling Pathway in Cardiomyocytes

Interleukin-18 Is a Pro-hypertrophic Cytokine That Acts through a Phosphatidylinositol 3-Kinase-Phosphoinositide-dependent Kinase-1-Akt-GATA4 Signaling Pathway in Cardiomyocytes

Overexpression of tumor necrosis factor (TNF)α and TNFα receptor I in human viral myocarditis: clinicopathologic correlations

Trypanosoma cruzi –Infected Cardiomyocytes Produce Chemokines and Cytokines That Trigger Potent Nitric Oxide–Dependent Trypanocidal Activity

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