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EDITORIAL FOCUS
: essential component to prevent myocardial oxidative stress?Cardiovascular Research Group, Departments of Pediatrics and Pharmacology, University of Alberta, Edmonton, Alberta, Canada
PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPARs) are among the 48 members of the nuclear receptor superfamily identified in the human genome (3). Three PPARs isoforms (
, 
/
, and 
) have been isolated. They are encoded by distinct genes and found to be distributed in various tissues, including heart, liver, skeletal muscles, and adipose tissue (11). After activation in the cytoplasm, PPARs bind to another transcription factor, the retinoid X receptor. These form a heterodimeric complex, which allows their transport into the nucleus and binding to a specific DNA sequence corresponding to the peroxisome proliferator response element (PPRE) localized in the promoter of the target gene. This process activates the transcription of the regulated gene (6).
PPAR plays an important role in lipid metabolism by regulating the expression of genes that encode proteins involved in the uptake and -oxidation of free fatty acids and cellular cholesterol trafficking (14). Therefore, PPAR is more widely expressed in tissues with high rates of mitochondrial fatty acid oxidation such as the heart (2). In addition, an anti-inflammatory activity of PPAR was also demonstrated (23). PPAR/ and PPAR play a major role in cellular differentiation processes. Additionally, PPARs contribute importantly to organogenesis regulated by retinoic acid, fatty acids, and their metabolites. They also regulate the development of fertilized embryonic cells and influence early steps of stem cell differentiation (12).
The mechanisms involved in the pathogenesis of heart failure are complex and involve the interaction of a number of cell types, including coronary endothelial cells, circulating blood cells, and cardiac myocytes, most of which are capable of generating reactive oxygen species (ROS) (1). ROS have the capability to damage both vascular cells and cardiac myocytes directly and can also initiate a series of chemical reactions and genetic alterations that ultimately result in cardiomyocyte dysfunction and/or death. The major ROS include superoxide anion (O2–), hydroxyl (HO
), H2O2, peroxynitrite (ONOO–), and its decomposition products (17). A delicate balance exists between the formation of these ROS and their removal by endogenous antioxidant compounds or enzymes, including glutathione, superoxide dismutase (SOD), catalase, and glutathione peroxidase. These protective mechanisms may be deficient because of disease, genetic derangement, or malnutrition or overwhelmed by various stressors. The net result is an excessive level of ROS leading to the impairment of myocardial contractility via various mechanisms, including activation of matrix metalloproteinase and poly-(ADP-ribose) polymerase activities, and oxidative damage to proteins, lipids and DNA resulting in the induction of apoptosis and/or necrosis in cardiac myocytes and other cells (17, 20).
The major role of PPAR in the heart is to provide energy to the myocardium by activating genes regulating mitochondrial fatty acid uptake and -oxidation (21). This results in the heart using fatty acid as the preferred substrate for energy production while retaining the ability to switch to glucose oxidation to meet its energy demands under varying dietary and/or pathophysiological conditions (19). However, there is a major controversy regarding changes in PPAR- activity in cardiac myopathies. Whether these are adaptive or causally related to myocardial pathology is unclear. For instance, in conditions of cardiac hypertrophy, PPAR- is downregulated, resulting in reversion of the heart to glucose utilization (19). Diminished cardiac fatty acid oxidation and increased glucose utilization has been found in studies of cardiac hypertrophy in both mice (18) and humans (4). This switch reduces the oxygen requirement of the heart to produce ATP molecules, which is higher per mole of fatty acid substrate oxidized than for glucose (21). In this context, the shift from PPAR--dependent fatty acid oxidation to glucose utilization can be considered as an adaptive response (9). In the long term, however, this switch becomes detrimental as less ATP is generated per mole of glucose oxidized, and lipid accumulation and lipotoxicity of the myocardium may develop (2). On the basis of these considerations whether this switch of energy substrates by deactivation of PPAR is actually an adaptive response or a mediator of the development of heart failure is not yet known (16).
In this issue of American Journal of Physiology-Heart and Circulatory Physiology, Guellich and colleagues (10) examined the role of oxidative stress damage in cardiac dysfunction of PPAR null mice. These authors demonstrate important and novel roles of PPAR in maintaining cardiac contractile performance and a homeostatic balance between ROS and antioxidants in the heart. PPAR deficiency was accompanied by a decrease in cardiac manganese SOD (MnSOD) expression and activity and a subsequent increase in oxidative/nitrosative damage, as evidenced by higher cardiac levels of 4-hydroxy-2-nonenal and 3-nitrotyrosine protein adducts. This decrease in both the expression and the activity of cardiac MnSOD will lead initially to an increase in O2– levels, which in turn will react with NO in an extremely fast diffusion-limited rate producing one of the most noxious cellular oxidants ONOO–. ONOO– is known as a mediator of cardiomyocyte damage (5, 15, 22) via different pathways including activation of matrix metalloproteinase, which likely is an immediate response to the initial oxidative stress, to protein nitration, which likely results from higher levels and/or extended exposure to ONOO– (17, 20). However, strong evidence of a direct interplay between cardiac MnSOD and PPAR is still lacking and whether the observation recorded is due to a lack of genuine regulation by PPAR or a long-term developmental adaptation to the absence of PPAR remains yet to be established. Moreover, in this study myosin heavy chain was found to be one of the major targets of protein tyrosine nitration in soluble heart extracts that may account for intrinsic myocardial contractile dysfunction in PPAR–/– mice. Likewise, the intrinsic papillary muscle performance was found to be depressed in PPAR–/– mice. Although histological data suggested that cardiomyocyte hypertrophy was pronounced in PPAR–/– mice, the heart weight-to-body weight ratio was not significantly different between wild-type and PPAR–/– mice. The authors thus speculated that a loss of cardiomyocytes in PPAR–/– mice had occurred presumably through apoptosis and/or fibrosis. Unfortunately, Guellich et al. did not directly address this possible correlation between cardiomyocyte cell death and PPAR deficiency.
These observations shed some light on the mechanisms of cardiac contractile dysfunction as a consequence of chronic PPAR deficiency. Whereas PPAR was mainly considered to serve a critical role in normal cardiac metabolic homeostasis (2), the data of Guellich and colleagues indicate that PPAR was also involved in the maintenance of cardiac oxidant/antioxidant balance. These results suggest the possible importance of PPAR in maintaining normal cardiac function by identifying oxidative damage to myosin as a link between PPAR deficiency and cardiac contractile dysfunction. It should be noted that PPAR has additional noncardiac effects on triglyceride and lipoprotein metabolism and antiatherosclerotic activity (8), which may further account into the cardiac dysfunction observed in PPAR–/– mice. Moreover, despite the cardioprotective effects of PPAR, several recent reports point to the possible unfavorable effects of PPAR activation in cardiomyocytes in Type 2 diabetes, metabolic syndrome, and obesity (6, 7, 13). Although much work still remains to be done in this area, the study by Guellich et al. indicates that PPAR as a ligand-activated transcription factor is an appealing candidate for pharmacological interventions aimed at the modulation of cardiac metabolism and oxidant-antioxidant homeostasis, which may ultimately prove useful as therapies for cardiovascular diseases.
FOOTNOTES
Address for reprint requests and other correspondence: R. Schulz, Cardiovascular Research Group, Univ. of Alberta, 4-62 HMRC, Edmonton, Alberta T6G 2S2, Canada (e-mail: richard.schulz{at}ualberta.ca)
REFERENCES
effects on the heart and other vascular tissues. Am J Physiol Heart Circ Physiol 285: H1–H9, 2003.–/– mice. Am J Physiol Heart Circ Physiol 292: H000–H000, 2007.This article has been cited by other articles:
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  A. H. Remels, H. R. Gosker, P. Schrauwen, R. C. Langen, and A. M. Schols Peroxisome proliferator-activated receptors: a therapeutic target in COPD? Eur. Respir. J., March 1, 2008; 31(3): 502 - 508. [Abstract] [Full Text] [PDF]
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 Y. Lecarpentier Physiological role of free radicals in skeletal muscles J Appl Physiol, December 1, 2007; 103(6): 1917 - 1918. [Full Text] [PDF]
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