Decreased cardiac mitochondrial NADP+-isocitrate dehydrogenase activity and expression: a marker of oxidative stress in hypertrophy development.

Abstract

Mitochondrial dysfunction subsequent to increased oxidative stress and alterations in energy metabolism is considered to play a role in the development of cardiac hypertrophy and its progression to failure, although the sequence of events remains to be elucidated. This study aimed at characterizing the impact of hypertrophy development on the activity and expression of mitochondrial NADP+-isocitrate dehydrogenase (mNADP+-ICDH), a metabolic enzyme that controls redox and energy status. We expanded on our previous finding of its inactivation through posttranslational modification by the lipid peroxidation product 4-hydroxynonenal (HNE) in 7-wk-old spontaneously hypertensive rat (SHR) hearts before hypertrophy development (Benderdour et al. J Biol Chem 278: 45154-45159, 2003). In this study, we used 7-, 15-, and 30-wk-old SHR and Sprague-Dawley (SD) rats with abdominal aortic coarctation. Compared with age-matched control Wistar-Kyoto (WKY) rats, SHR hearts showed a significant 25% decrease of mNADP+-ICDH activity, which preceded in time 1) the decline in its protein and mRNA expression levels (between 10% and 35%) and 2) the increase in hypertrophy markers. The chronic and persistent loss of mNADP+-ICDH activity in SHR was associated with enhanced tissue accumulation of HNE-mNADP+-ICDH and total HNE-protein adducts at all ages and contrasted with the profile of changes in the activity of other mitochondrial enzymes involved in antioxidant or energy metabolism. Two-way ANOVA of the data also revealed a significant effect of age on most parameters measured in SHR and WKY hearts. The mNADP+-ICDH activity, protein, and mRNA expression were reduced between 25% and 35% in coarctated SD rats and were normalized by treatment of SHR or coarctated SD rats with renin-angiotensin system inhibitors, which prevented or attenuated hypertrophy. Altogether, our data show that cardiac mNADP+-ICDH activity and expression are differentially and sequentially affected in hypertrophy development and, to a lesser extent, with aging. Decreased cardiac mNADP+-ICDH activity, which is attributed at least in part to HNE adduct formation, appears to be a relevant early and persistent marker of mitochondrial oxidative stress-related alterations in hypertrophy development. Potentially, this could also contribute to the aetiology of cardiomyopathy.

• Authors: Mohamed Benderdour, Guy Charron, Blandine Comte, Riwa Ayoub, Diane Beaudry, Sylvain Foisy, Denis Deblois, Christine Des Rosiers
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 287 Issue 5 Pg. H2122-31 (Nov 2004) ISSN: 0363-6135 [Print] United States
• PMID: 15271667 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aldehydes
• Angiotensin-Converting Enzyme Inhibitors
• Biomarkers
• NADP
• Enalapril
• Isocitrate Dehydrogenase
• Superoxide Dismutase
• 4-hydroxy-2-nonenal

Topics

• Aldehydes (metabolism)
• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Animals
• Aortic Coarctation (complications, enzymology)
• Biomarkers (metabolism)
• Cardiomegaly (etiology, metabolism)
• Enalapril (pharmacology)
• Hypertension (complications, enzymology, genetics)
• Isocitrate Dehydrogenase (metabolism)
• Male
• Mitochondria, Heart (enzymology)
• NADP (metabolism)
• Oxidative Stress
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Renin-Angiotensin System (drug effects)
• Superoxide Dismutase (metabolism)