PPAR-gamma agonists decrease hyperhomcysteinemia and cardiac dysfunction: new hope for ailing diabetic hearts?
نویسندگان
چکیده
THE PEROXISOME proliferator-activated receptor(PPAR) family of nuclear hormone receptors has been extensively studied due to its antidiabetic, anti-inflammatory, and antiatherosclerotic actions. PPARheterodimerizes with the retinoid X receptor to regulate transcription of target genes by binding to specific peroxisome proliferator-response elements. Structurally diverse ligands activate PPAR, including eicosanoids, 15-deoxy-prostaglandin J2, and antidiabetic thiazolidinedione drugs, such as troglitazone, ciglitazone, pioglitazone, and rosiglitazone (18). PPARcontrols adipocyte differentiation and regulates the actions of insulin on adipose tissue and skeletal muscle (13). Therefore, ligands that activate PPARare widely used as insulin-sensitizing agents in treatment of noninsulin-dependent diabetes mellitus. Increasing evidence suggests that PPARactivators impact the cardiovascular system through not only their lipidand carbohydrate-lowering effects but also their anti-inflammatory and antioxidant actions. In general, the effects of PPARagonists, such as pioglitazone, on HDL cholesterol and triglycerides are associated with their antiatherosclerotic actions, whereas the nonlipid effects on inflammatory cytokine production and oxidative stress are thought to underlie the ability of PPARagonists to lower blood pressure and improve endothelial dysfunction (see Ref. 20 for an excellent review). The metabolism-independent effects of PPARactivators in the heart are somewhat more controversial. Schriffin’s group (9) reported that the PPARactivator pioglitazone has beneficial, long-term effects on cardiac hypertrophy and cardiac inflammation but had no effect on cardiac function in strokeprone spontaneously hypertensive rats. A novel PPARagonist, 2-[2-(phenoxy-2-propylphenoxy)-ethyl]indole-5-acetic acid, had no effect on contractile function in Type 2 diabetic db/db mice despite improved insulin-stimulated glucose uptake, increased glucose oxidation, and decreased fatty acid oxidation (5). On the other hand, pioglitazone and rosiglitazone have been shown to improve left ventricular (LV) systolic and diastolic function in response to mitral valve regurgitation (15) and acute ischemia in nondiabetic pigs (24) and reduced cardiac fibrosis on DOCA-salt hypertensive rats (11). In this issue of American Journal of Physiology-Heart and Circulatory Physiology, Rodriguez et al. (17) report that pioglitazone treatment of mice fed a high-fat diet improved diabetes-induced cardiac remodeling, contractile dysfunction, and hypertension. These beneficial effects were associated with reduced tissue (but not plasma) homocysteine (Hcy), decreased matrix metalloproteinase (MMP)-2/9 activation and expression, increased tissue nitric oxide (NO) production, and improved endothelial-myocyte coupling. Although this group (21) and others have linked reduction in plasma Hcy levels to PPARagonists (14), this is the first study to link PPARactivation with reduction in cardiac tissue Hcy levels in a diabetic model. The reduction in tissue Hcy may represent an additional mechanism by which PPARactivators improve structure and function in the ailing, diabetic myocardium. A recent study (19) of patients with Type 2 diabetes reported that increased plasma levels of Hcy were associated with increased incidence of ischemic heart disease, hypertension, and coronary artery disease. However, the study by Rodriguez et al. (17) suggests that decreased tissue levels of Hcy may have a more important influence than plasma Hcy levels on local properties of the diabetic myocardium, such as endothelialmyocyte coupling, chamber remodeling, and NO bioavailability. Hyperhomocysteinemia is linked to adverse cardiac remodeling and contractile dysfunction in both human and animal models. A recent prospective investigation (7) of hypertensive and normotensive patients in the Genetic and Environmental Factors in Coronary Atherosclerosis (GENICA) suggested that increased plasma levels of Hcy are inversely related to LV ejection fraction and directly predict increased cardiovascular mortality in patients with high-risk coronary artery disease hypertension. Tyagi’s group (6) has already reported that Hcy mediates cardiac remodeling and disruption of endothelial myocyte coupling in the two-kidney, one-clip Goldblatt hypertensive mouse model and extracellular matrix (ECM) remodeling in homocysteinemic obese rabbits. Moreover, daily injections of Hcy for 14 days in normal rats significantly decreased posterior wall thickness, increased LV in diastolic and systolic dimensions, and decreased fractional shortening (23). Another important observation in the Rodriguez et al. (17) study is that diabetes-induced diastolic dysfunction [decreased first derivative of pressure ( dP/dt) and reduced relaxation in response to acetylcholine and NO donors] was associated with endothelial-myocyte uncoupling. The modulatory effects of the endocardial and capillary endothelium on cardiac contractile function, growth, metabolism, and rhythmicity are well known (see Ref. 3 for a comprehensive review). The mechanisms that link Hcy and PPARagonists to improved LV remodeling and endothelial-myocardial coupling have not been extensively characterized. However, a common denominator may be endothelial dysfunction secondary to increased oxidative stress and reduced NO bioavailability. Indeed, Hcy increases the expression of the p22 subunit of NAD(P)H oxidase in LV tissue as well as promoting assembly of the NAD(P)H oxidase subunits (2). This was related to an inhibition of NO-dependent regulation of cardiac oxygen consumption, which can be restored by antioxidants (2). The general paradigm appears to be that local, paracrine release of endothelium-derived NO, endothelin-1 (ET-1), and ANG II, prostaglandins, and endotheliumderived hyperpolarizing factor modulate the contractile properties of adjacent myocytes. Address for reprint requests and other correspondence: P. A. Lucchesi, Dept. of Pharmacology, LSU Health Sciences Center, 1901 Perdido St., MEB-5240, New Orleans, LA 70112 (e-mail: [email protected]). Am J Physiol Heart Circ Physiol 291: H26–H28, 2006; doi:10.1152/ajpheart.00277.2006.
منابع مشابه
PPAR- agonists decrease hyperhomcysteinemia and cardiac dysfunction: new hope for ailing diabetic hearts?
THE PEROXISOME proliferator-activated receptor(PPAR) family of nuclear hormone receptors has been extensively studied due to its antidiabetic, anti-inflammatory, and antiatherosclerotic actions. PPARheterodimerizes with the retinoid X receptor to regulate transcription of target genes by binding to specific peroxisome proliferator-response elements. Structurally diverse ligands activate PPAR, i...
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عنوان ژورنال:
- American journal of physiology. Heart and circulatory physiology
دوره 291 1 شماره
صفحات -
تاریخ انتشار 2006