Abstract
ObjectiveCarnitine 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-γ expression in Shunt lambs. Thus, this study was carried out to determine if there is a causal link between loss of PPAR-γ signaling and carnitine dysfunction, and whether the PPAR-γ agonist, rosiglitazone preserves carnitine homeostasis in Shunt lambs.Methods and ResultssiRNA-mediated PPAR-γ 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.ConclusionOur study indicates that PPAR-γ 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-γ regulates NO signaling through Hsp90. Thus, PPAR-γ agonists may have therapeutic potential in preventing the endothelial dysfunction in children with increased pulmonary blood flow.
Highlights
Carnitine is present in the form of either free carnitine, or acyl carnitines
Our study indicates that Peroxisome proliferator-activated receptors (PPARs)-c signaling plays an important role in maintaining mitochondrial function through the regulation of carnitine homeostasis both in vitro and in vivo
PPAR-c binding activity was significantly decreased in PPAR-c small interfering RNA (siRNA) transfected cells, and this was reversed after treatment with the PPAR-c agonist, rosiglitazone (Figure 1 B)
Summary
Carnitine is present in the form of either free carnitine (nonesterified molecule; FC), or acyl carnitines (esterified form; AC). A low AC/FC ratio is indicative of healthy mitochondria whereas a high AC/FC ratio suggests a decreased mitochondrial capacity for energy production. Carnitine and its derivatives are involved in the mitochondrial transport of fatty acids and are critical for the cell to maintain normal mitochondrial function. It is well established that the disruption of carnitine metabolism leads to mitochondrial dysfunction in cells. Our previous studies have identified a progressive endothelial dysfunction in a lamb model (Shunt) that mimics congenital heart disease with increased pulmonary blood flow [1]. This correlated with decreased expression and activity of mitochondrial enzymes involved in carnitine metabolism, disrupted carnitine homeostasis, and mitochondrial dysfunction [2]
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