Activation of peroxisome proliferator‐activated receptor‐α and ‐γ in auricular tissue from heart failure patients

Abstract

Objective: Peroxisome proliferator-activated receptors (PPARs), key transcriptional regulators of lipid and energy metabolism in cardiomyocytes, have recently been proposed to modulate cardiovascular pathophysiological responses in experimental models. However, there is little information about the functional activity of PPARs in human heart failure. Aims: To investigate PPAR-a and -g expression and activity, and the association with ET-1 production and fibrosis, in cardiac biopsies from patients with end-stage heart failure due to ischemic cardiomyopathy (ICM) in comparison and from non-failing donor hearts. All samples were obtained during cardiac transplantation. Methods and results: Morphological analysis (by Masson trichrome and image analysis) did not detect fibrosis in the left atrium from nonfailing donors (NFLA) or from ICM patients (FLA). However, left ventricles from failing hearts (FLV) contained a greater number of fibrotic areas (NFLA: 3.21 T1.15, FLA: 1.63 T 0.83, FLV: 14.5 T 3.45%; n = 9, P < 0.05). By RT-PCR, preproET-1 expression was similar in the nonfailing and failing atrium but was significantly higher in the ventricles from failing hearts (NFLA: 1.00 T 0.06, FLA: 1.08 T 0.11, FLV: 1.74 T 0.19; n = 9, P < 0.05). PPAR-a and PPAP-g mRNA (by RT-PCR) and protein (by Western blot) levels were higher in the ventricles from failing hearts compared with the atrium from failing and non-failing hearts. Electrophoretic mobility shift assays showed that PPAR-a and PPAP-g were not activated in the ventricles (NFLA: 1.00 T 0.11, FLA: 1.89 T 0.24, FLV: 0.95 T 0.07; n = 9, P < 0.05). Conclusions: These data suggest that PPAR-a and PPAP-g are selectively activated in the atria from ICM patients and might be functionally important in the maintenance of atrial morphology.

PPAR-γ expression in animals subjected to volume overload and chronic Urotensin II administration

“…This is the first study using a well-recognized animal model of heart failure to measure changes in PPAR-γ expression and activity. The data presented here, however, follow well with that observed by Gomez-Garre et al [9]. In their study, the researchers measured PPAR-γ expression in left ventricles of patients with endstage heart failure due to ischemic cardiomyopathy.…”

“…Additionally, the use of glitazones, agents which activate PPAR-γ, are tolerated in all but late stage patients, presumably due to increased fluid retention [16]. It is currently unclear however, how the expression of PPAR-γ as well as its activity is altered with the progression of disease, though recent data has suggested that in human auricular tissue PPAR-γ mRNA and protein expression is increased in patients with ischemic cardiomyopathy [9].…”

Insulin-Sensitizing Effect of LXR Agonist T0901317 in High-Fat Fed Rats is Associated with Restored Muscle GLUT4 Expression and Insulin-Stimulated AS160 Phosphorylation

“…AS160 is a downstream substrate of Akt/PKB that plays a key role in mediating the translocation of GLUT4 to the plasma membrane in response to insulin [21]. It was found that the ability of insulin to stimulate AS160 phosphorylation is impaired in insulin-resistant skeletal muscle, and that this impairment is ameliorated by interventions leading to improved insulin sensitivity [22,23].…”

Peroxisome Proliferator-Activated Receptors at the Crossroads of Obesity, Diabetes, and Cardiovascular Disease

“…In an in vitro cardiac-hypertrophy model, the PPAR␣ agonists fenofibrate and Wy-14,643 and the PPAR␤/␦ agonist L165041 reduced hypertrophy, although the expression of both PPAR␣ and PPAR␤/␦ were found to be decreased during hypertrophy (108). In contrast, in humans it was observed that protein expression of both PPAR␣ and PPAR␥ were increased in failing left ventricle (109). Cardiomyocyte-specific knockout of PPAR␤/␦ resulted in lipotoxic dilated cardiomyopathy caused by a decreased expression of fatty acid handling genes (110).…”