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Cardiac oxidative stress in a mouse model of neutral lipid storage disease.

Schrammel A, Mussbacher M, Winkler S, Haemmerle G, Stessel H, Wölkart G, Zechner R, Mayer B - Biochim. Biophys. Acta (2013)

Bottom Line: Systemic deletion of the gene encoding adipose triglyceride lipase (ATGL), the enzyme that catalyzes the rate-limiting step of triglyceride lipolysis, results in a phenotype characterized by severe steatotic cardiac dysfunction.Investigating the effect of oxidative and inflammatory stress on nitric oxide/cGMP signal transduction we observed a ~2.5-fold upregulation of soluble guanylate cyclase activity and a ~2-fold increase in cardiac tetrahydrobiopterin levels.Upregulation of soluble guanylate cyclase and cardiac tetrahydrobiopterin might be regarded as counterregulatory mechanisms in cardiac ATGL deficiency.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, University of Graz, Universitätsplatz 2, 8010 Graz, Austria. Electronic address: astrid.schrammel-gorren@uni-graz.at.

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Signaling pathways that link cardiac ATGL deficiency to oxidative inflammatory stress and increased sGC activity. Impaired PPARα signaling in ATGL deficiency induces cardiac hypertrophy (path 1) that is compensated by increased sGC activity (path 6). Impaired PPARα signaling leads to increased superoxide production by NADPH oxidases (path 2) and augmented expression of inflammatory markers (path 3). Elevated TNFα levels induce expression of cardiac NADPH oxidases via activation of PKC (path 4). Lipid droplet surface-binding proteins directly initiate oxidative and inflammatory processes (path 5). NADPH oxidase-generated superoxide scavenges NO to form ONOO− (path 7). Reduced NO availability induces activation of cardiac sGC. NADPH oxidase-derived superoxide production enhances cardiac hypertrophy and contractile dysfunction (path 8).
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sch0005: Signaling pathways that link cardiac ATGL deficiency to oxidative inflammatory stress and increased sGC activity. Impaired PPARα signaling in ATGL deficiency induces cardiac hypertrophy (path 1) that is compensated by increased sGC activity (path 6). Impaired PPARα signaling leads to increased superoxide production by NADPH oxidases (path 2) and augmented expression of inflammatory markers (path 3). Elevated TNFα levels induce expression of cardiac NADPH oxidases via activation of PKC (path 4). Lipid droplet surface-binding proteins directly initiate oxidative and inflammatory processes (path 5). NADPH oxidase-generated superoxide scavenges NO to form ONOO− (path 7). Reduced NO availability induces activation of cardiac sGC. NADPH oxidase-derived superoxide production enhances cardiac hypertrophy and contractile dysfunction (path 8).

Mentions: Different explanations are conceivable to link ATGL deficiency to oxidative inflammatory stress and increased sGC activity (Scheme 1). Conceivably, severely impaired peroxisome proliferator receptor α (PPARα) signaling in ATGL deficiency [38] may initiate a sequelae of events that eventually lead to the observed effects. Thus, downregulation of PPARα signaling has been demonstrated to favor the development of cardiomyocyte hypertrophy ([39], path 1). Interestingly, mice lacking PPARα have been described to develop cardiac dysfunction due to oxidative stress ([40], path 2). Moreover, the PPARα-deficient cardiac phenotype is characterized by enhanced expression of proinflammatory and fibrotic markers [39] not unlike our observations with ATGL(−/−) mice (path 3). Elevation of cardiac TNFα levels has been associated with enhanced expression/activation of NADPH oxidases in the course of chronic ventricular remodeling ([41], path 4).


Cardiac oxidative stress in a mouse model of neutral lipid storage disease.

Schrammel A, Mussbacher M, Winkler S, Haemmerle G, Stessel H, Wölkart G, Zechner R, Mayer B - Biochim. Biophys. Acta (2013)

Signaling pathways that link cardiac ATGL deficiency to oxidative inflammatory stress and increased sGC activity. Impaired PPARα signaling in ATGL deficiency induces cardiac hypertrophy (path 1) that is compensated by increased sGC activity (path 6). Impaired PPARα signaling leads to increased superoxide production by NADPH oxidases (path 2) and augmented expression of inflammatory markers (path 3). Elevated TNFα levels induce expression of cardiac NADPH oxidases via activation of PKC (path 4). Lipid droplet surface-binding proteins directly initiate oxidative and inflammatory processes (path 5). NADPH oxidase-generated superoxide scavenges NO to form ONOO− (path 7). Reduced NO availability induces activation of cardiac sGC. NADPH oxidase-derived superoxide production enhances cardiac hypertrophy and contractile dysfunction (path 8).
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3795454&req=5

sch0005: Signaling pathways that link cardiac ATGL deficiency to oxidative inflammatory stress and increased sGC activity. Impaired PPARα signaling in ATGL deficiency induces cardiac hypertrophy (path 1) that is compensated by increased sGC activity (path 6). Impaired PPARα signaling leads to increased superoxide production by NADPH oxidases (path 2) and augmented expression of inflammatory markers (path 3). Elevated TNFα levels induce expression of cardiac NADPH oxidases via activation of PKC (path 4). Lipid droplet surface-binding proteins directly initiate oxidative and inflammatory processes (path 5). NADPH oxidase-generated superoxide scavenges NO to form ONOO− (path 7). Reduced NO availability induces activation of cardiac sGC. NADPH oxidase-derived superoxide production enhances cardiac hypertrophy and contractile dysfunction (path 8).
Mentions: Different explanations are conceivable to link ATGL deficiency to oxidative inflammatory stress and increased sGC activity (Scheme 1). Conceivably, severely impaired peroxisome proliferator receptor α (PPARα) signaling in ATGL deficiency [38] may initiate a sequelae of events that eventually lead to the observed effects. Thus, downregulation of PPARα signaling has been demonstrated to favor the development of cardiomyocyte hypertrophy ([39], path 1). Interestingly, mice lacking PPARα have been described to develop cardiac dysfunction due to oxidative stress ([40], path 2). Moreover, the PPARα-deficient cardiac phenotype is characterized by enhanced expression of proinflammatory and fibrotic markers [39] not unlike our observations with ATGL(−/−) mice (path 3). Elevation of cardiac TNFα levels has been associated with enhanced expression/activation of NADPH oxidases in the course of chronic ventricular remodeling ([41], path 4).

Bottom Line: Systemic deletion of the gene encoding adipose triglyceride lipase (ATGL), the enzyme that catalyzes the rate-limiting step of triglyceride lipolysis, results in a phenotype characterized by severe steatotic cardiac dysfunction.Investigating the effect of oxidative and inflammatory stress on nitric oxide/cGMP signal transduction we observed a ~2.5-fold upregulation of soluble guanylate cyclase activity and a ~2-fold increase in cardiac tetrahydrobiopterin levels.Upregulation of soluble guanylate cyclase and cardiac tetrahydrobiopterin might be regarded as counterregulatory mechanisms in cardiac ATGL deficiency.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, University of Graz, Universitätsplatz 2, 8010 Graz, Austria. Electronic address: astrid.schrammel-gorren@uni-graz.at.

Show MeSH
Related in: MedlinePlus