Cardiac oxidative stress in a mouse model of neutral lipid storage disease.
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.
Affiliation: Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, University of Graz, Universitätsplatz 2, 8010 Graz, Austria. Electronic address: email@example.com.Show MeSH
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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  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 (, path 1). Interestingly, mice lacking PPARα have been described to develop cardiac dysfunction due to oxidative stress (, path 2). Moreover, the PPARα-deficient cardiac phenotype is characterized by enhanced expression of proinflammatory and fibrotic markers  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 (, path 4).
Affiliation: Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, University of Graz, Universitätsplatz 2, 8010 Graz, Austria. Electronic address: firstname.lastname@example.org.