Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response

Abstract

. Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response. Am J Physiol Endocrinol Metab 286: E201-E207, 2004; 10.1152/ ajpendo.00205.2003.-Severe sepsis results in the decreased uptake and oxidation of fatty acids in the heart and cardiac failure. Some of the key proteins required for fatty acid uptake and oxidation in the heart have been shown to be downregulated after endotoxin (LPS) administration. The nuclear hormone receptors, peroxisome proliferator-activated receptor (PPAR) and thyroid receptor (TR), which heterodimerize with the retinoid X receptor (RXR), are important regulators of fatty acid metabolism and decrease in the liver after LPS administration. In the present study, we demonstrate that LPS treatment produces a rapid and marked decrease in the mRNA levels of all three RXR isoforms, PPAR␣ and PPAR␦, and TR␣ and TR␤ in the heart. Moreover, LPS administration also decreased the expression of the coactivators CREB-binding protein (CBP)/p300, steroid receptor coactivator (SRC)-1, SRC-3, TR-associated protein (TRAP)220, and PPAR␥ coactivator (PGC)-1, all of which are required for the transcriptional activity of RXR-PPAR and RXR-TR. In addition, the mRNA levels of the target genes malic enzyme, Spot 14, sarcoplasmic reticulum Ca 2ϩ -ATPase, or SERCA2, the VLDL receptor, fatty acylCoA synthetase, fatty acid transporter/CD36, carnitine palmitoyltransferase I␤, and lipoprotein lipase decrease in the heart after LPS treatment. The decrease in expression of RXR␣, -␤, and -␥, PPAR␣ and -␦, and TR␣ and -␤, and of the coactivators CBP/p300, SRC-1, SRC-3, TRAP220, and PGC-1 and the genes they regulate, induced by LPS in the heart, could account for the decreased expression of key proteins required for fatty acid oxidation and thereby play an important role in cardiac contractility. These alterations could contribute to the myocardial dysfunction that occurs during sepsis. endotoxin; fatty acid oxidation; cardiac contractility SEVERE SEPSIS RESULTS IN CARDIAC FAILURE, and this effect can be mimicked by endotoxin (LPS) administration (11,48,50,56). Initially, during sepsis and after LPS administration, there is a decrease in systemic resistance and either normal or increased cardiac output (11,48,50,56). However, with time, cardiac output decreases due to a decrease in both contractility and heart rate (11,48,50,56). Similar effects on cardiac function are observed with the administration of TNF and IL-1 (7,42,44,47), cytokines that mediate the effects of LPS (7,15).For the heart to function as a pump, constant generation of ATP is required, which is formed by the oxidation of fatty acids, glucose, or lactate (59). Fatty acid oxidation produces the most energy per molecule, and because of the high-energy demands of the heart, fatty acids are the primary fuel for cardiac ATP generation (58, 59). The oxidation of fatty acids by cardiac myocytes involves a large number of enzymes and transporters. One of the initial steps is the hydrolysis of triglycerides c...

Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-γ coactivator 1α

“…As mentioned above, the expression of PGC-1␣ and many of its target genes is repressed in various rodent models of cardiac failure (28)(29)(30)(31)(32)(33)(34)(35)(36). Consistent with these findings, PGC-1␣ was repressed by Ϸ30-40% in WT mice subjected to TAC, compared with WT controls (Fig.…”

“…This finding suggests that a threshold of mitochondrial activity might be required to cope with chronic hemodynamic load, and that the combination of PGC-1␣ repression and aortic banding hastens the falling below that threshold. Repression of PGC-1␣ and genes regulated by PGC-1␣ is also observed in other models of heart failure, even in cases where mitochondrial defects or pressure overload are not the primary etiology of cardiac dysfunction (28)(29)(30)(31)(32)(33)(34)(35)(36). Hence, the data suggest that, even in these cases, repression of PGC-1␣ may be causally involved in the development of heart failure.…”

“…A growing literature indicates that PGC-1␣ expression is altered in experimental models of heart disease (28)(29)(30)(31)(32)(33)(34)(35)(36). For example, PGC-1␣ and mitochondrial genes that are regulated by PGC-1␣ are repressed in rodent models of cardiac hypertrophy (30,31,37).…”

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

“…In heart, kidney, and liver, PGC-1, ERR and MCAD mRNA was markedly reduced 16h after LPS injection [279]. Furthermore, in cardiac tissue, inflammation-dependent PGC-1 repression was further confirmed in vitro and in vivo, which could be rescued by inhibiting the NF-B pathway [280][281][282]. Sepsisassociated acute kidney injury is associated with swollen, dysfunctional mitochondria and reduced PGC-1 levels that correlate with renal impairment [283].…”

Retinoid X receptors: common heterodimerization partners with distinct functions

“…or cytokine treatment in rodent heart and liver 34 . Interestingly, Rxra, Rxrb and Rxrg expression does not follow a rhythmic cycle of expression in metabolically active tissues from C57Bl/6 mice, with the exception of Rxra in liver, and in opposition to a number of other RXR dimerization partners such as FXR, PPARs and RARs 35 .…”