A role for Sp and nuclear receptor transcription factors in a cardiac hypertrophic growth program

Abstract

During cardiac hypertrophy, the chief myocardial energy source switches from fatty acid ␤-oxidation (FAO) to glycolysis-a reversion to fetal metabolism. The expression of genes encoding myocardial FAO enzymes was delineated in a murine ventricular pressure overload preparation to characterize the molecular regulatory events involved in the alteration of energy substrate utilization during cardiac hypertrophy. Expression of genes involved in the thioesterification, mitochondrial import, and ␤-oxidation of fatty acids was coordinately down-regulated after 7 days of right ventricular (RV) pressure overload. Results of RV pressure overload studies in mice transgenic for the promoter region of the gene encoding human medium-chain acyl-CoA dehydrogenase (MCAD, which catalyzes a rate-limiting step in the FAO cycle) fused to a chloramphenicol acetyltransferase reporter confirmed that repression of MCAD gene expression in the hypertrophied ventricle occurred at the transcriptional level. Electrophoretic mobility-shift assays performed with MCAD promoter fragments and nuclear protein extracts prepared from hypertrophied and control RV identified pressure overload-induced protein͞DNA interactions at a regulatory unit shown previously to confer control of MCAD gene transcription during cardiac development. Antibody ''supershift'' studies demonstrated that members of the Sp (Sp1, Sp3) and nuclear hormone receptor [chicken ovalbumin upstream promoter transcription factor (COUP-TF)͞erbA-related protein 3] families interact with the pressure overload-responsive unit. Cardiomyocyte transfection studies confirmed that COUP-TF repressed the transcriptional activity of the MCAD promoter. The DNA binding activities and nuclear expression of Sp1͞3 and COUP-TF in normal fetal mouse heart were similar to those in the hypertrophied adult heart. These results identify a transcriptional regulatory mechanism involved in the reinduction of a fetal metabolic program during pressure overload-induced cardiac hypertrophy.Fatty acid oxidation (FAO) is the major source of energy in the adult mammalian heart (1). The chief myocardial energy source switches from glucose and pyruvate in the fetal period to fatty acids after birth (1, 2). Studies in a variety of mammalian species, including humans, have shown that with cardiac hypertrophy, myocardial glucose utilization increases and FAO decreases: a reinduction of the fetal energy metabolic program (3-8). Myocardial energy utilization pathways also undergo alterations during cardiac hypertrophy, as evidenced by the re-expression of the fetal isoforms of a variety of ATPases involved in contractile function (e.g., myosin heavy chains) and ion homeostasis (e.g., Ca 2ϩ -and Na ϩ -K ϩ ATPases) (9-16). Accordingly, reactivation of fetal gene regulatory programs in the hypertrophied heart may serve to reduce ATP and oxygen consumption requirements, albeit at a cost of diminished energy-producing capacity and contractile reserve. Little is known about the molecular regulatory mechanisms involved in...

Peroxisome proliferator-activated receptor .ALPHA. (PPAR.ALPHA.) agonist, WY-14,643, increased transcription of myosin light chain-2 in cardiomyocytes.

“…These results from the 26-week experiment in vivo suggest that WY-14,643 directly increases the amount of protein in rat hearts, because it had this effect on H9c2 cells, a cardiomyocyte cell line. Sack et al (1997) reported that the amount of nuclear PPAR is decreased in a hypertrophied heart. The same group also reported that PPAR is deactivated during the -adrenergic agonistinduced hypertrophic growth in an overexpressed recombinant PPAR system (Barger et al, 2000).…”

“…Nothing, however, is known with regard to the potential role of PPAR in the pathology of cardiac tissue (Bishop-Bailey, 2000). Sack et al (1997) reported that the amount of nuclear PPAR decreases in the hypertrophied mouse heart. Barger et al (2000) reported that PPAR is deactivated by several times, leading to diminished capacity for myocardial lipid and energy homeostasis duringadrenergic agonist-induced cardiac hypertrophic growth in rat neonatal cardiac myocyte.…”

PPAR-α effects on the heart and other vascular tissues

“…In conditions of pressure-induced cardiac hypertrophy, PPAR-␣ is downregulated, resulting in reversion of the heart to the fetal pattern of glucose and lactate substrate utilization (4,74). Diminished cardiac FAO and increased utilization of glucose has been found in studies of both murine (73) and human (19) cardiac hypertrophy. This switch reduces the oxygen requirement of the heart to produce ATP, which is higher per mole of fatty acid substrate oxidized than for glucose (94).…”

The Effects of Biological Sex and Diet on the Development of Heart Failure

“…Specifically, SIRT1 deacetylates PPAR␥ coactivator 1␣ (PGC-1␣), a critical regulator of mitochondrial oxidative metabolism and the maintenance of glucose, lipid, and energy homeostasis, increasing its transcriptional activity. 176 In human and rat CHF 177,178 and in murine models of pressure overload, 179,180 metabolic dysregulation occurs in the heart that is characterized by marked reduction in mitochondrial oxidative metabolism rates with a concomitant shift to increased glucose utilization placing PGC-1␣ in a key position to mediate this process. In fact, the loss of PGC-1␣ results in early symptoms of heart failure in mice.…”