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: firstname.lastname@example.org.Show MeSH
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Mentions: Oxidative stress generated in the course of different vascular and metabolic disorders may cause depletion of the essential NOS cofactor BH4[25–27]. Reduced intracellular availability of BH4 leads to uncoupling of NOS i.e. the production of superoxide instead of NO, thereby aggravating the oxidative burden. To investigate whether this occurs in ATGL deficiency, we measured cardiac biopterin levels. Paradoxically, BH4 levels were actually increased ~ 2-fold in ATGL deficiency (Fig. 5A). In hearts, exclusively overexpressing ATGL in cardiomyocytes, BH4 values were comparable to those of WT animals. By contrast, cardiac BH2 was not significantly affected by any genetic manipulation (Fig. 5B). Calculations of the BH4/BH2 ratio showed a tendency towards increased values in ATGL deficiency; however, the difference did not reach statistical significance (Fig. 5C).
Affiliation: Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, University of Graz, Universitätsplatz 2, 8010 Graz, Austria. Electronic address: email@example.com.