PPAR-c Regulates Carnitine Homeostasis and Mitochondrial Function in a Lamb Model of Increased Pulmonary Blood Flow
Oishi, Peter E.
Datar, Sanjeev A.
Fineman, Jeffrey R.
Black, Stephen M.
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AbstractObjective: Carnitine homeostasis is disrupted in lambs with endothelial dysfunction secondary to increased pulmonary blood flow (Shunt). Our recent studies have also indicated that the disruption in carnitine homeostasis correlates with a decrease in PPAR-c expression in Shunt lambs. Thus, this study was carried out to determine if there is a causal link between loss of PPAR-c signaling and carnitine dysfunction, and whether the PPAR-c agonist, rosiglitazone preserves carnitine homeostasis in Shunt lambs.
Methods and Results: siRNA-mediated PPAR-c knockdown significantly reduced carnitine palmitoyltransferases 1 and 2 (CPT1 and 2) and carnitine acetyltransferase (CrAT) protein levels. This decrease in carnitine regulatory proteins resulted in a disruption in carnitine homeostasis and induced mitochondrial dysfunction, as determined by a reduction in cellular ATP levels. In turn, the decrease in cellular ATP attenuated NO signaling through a reduction in eNOS/Hsp90 interactions and enhanced eNOS uncoupling. In vivo, rosiglitazone treatment preserved carnitine homeostasis and attenuated the development of mitochondrial dysfunction in Shunt lambs maintaining ATP levels. This in turn preserved eNOS/Hsp90 interactions and NO signaling.
Conclusion: Our study indicates that PPAR-c signaling plays an important role in maintaining mitochondrial function through the regulation of carnitine homeostasis both in vitro and in vivo. Further, it identifies a new mechanism by which PPAR-c regulates NO signaling through Hsp90. Thus, PPAR-c agonists may have therapeutic potential in preventing the endothelial dysfunction in children with increased pulmonary blood flow.
CitationPLoS One. 2012 Sep 4; 7(9):e41555
- Altered carnitine homeostasis is associated with decreased mitochondrial function and altered nitric oxide signaling in lambs with pulmonary hypertension.
- Authors: Sharma S, Sud N, Wiseman DA, Carter AL, Kumar S, Hou Y, Rau T, Wilham J, Harmon C, Oishi P, Fineman JR, Black SM
- Issue date: 2008 Jan
- Disruption of endothelial cell mitochondrial bioenergetics in lambs with increased pulmonary blood flow.
- Authors: Sun X, Sharma S, Fratz S, Kumar S, Rafikov R, Aggarwal S, Rafikova O, Lu Q, Burns T, Dasarathy S, Wright J, Schreiber C, Radman M, Fineman JR, Black SM
- Issue date: 2013 May 10
- Role of carnitine acetyl transferase in regulation of nitric oxide signaling in pulmonary arterial endothelial cells.
- Authors: Sharma S, Sun X, Agarwal S, Rafikov R, Dasarathy S, Kumar S, Black SM
- Issue date: 2012 Dec 21
- L-carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow.
- Authors: Sharma S, Aramburo A, Rafikov R, Sun X, Kumar S, Oishi PE, Datar SA, Raff G, Xoinis K, Kalkan G, Fratz S, Fineman JR, Black SM
- Issue date: 2013 Jul
- Chronic inhibition of PPAR-γ signaling induces endothelial dysfunction in the juvenile lamb.
- Authors: Sharma S, Barton J, Rafikov R, Aggarwal S, Kuo HC, Oishi PE, Datar SA, Fineman JR, Black SM
- Issue date: 2013 Apr
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