Fatty acid oxidation and malonyl-CoA decarboxylase in the vascular remodeling of pulmonary hypertension.

Pulmonary arterial hypertension is caused by excessive growth of vascular cells that eventually obliterate the pulmonary arterial lumen, causing right ventricular failure and premature death. Despite some available treatments, its prognosis remains poor, and the cause of the vascular remodeling remains unknown. The vascular smooth muscle cells that proliferate during pulmonary arterial hypertension are characterized by mitochondrial hyperpolarization, activation of the transcription factor NFAT (nuclear factor of activated T cells), and down-regulation of the voltage-gated potassium channel Kv1.

Distinct early signaling events resulting from the expression of the PRKAG2 R302Q mutant of AMPK contribute to increased myocardial glycogen.

Background: Humans with an R302Q mutation in AMPKgamma(2) (the PRKAG2 gene) develop a glycogen storage cardiomyopathy characterized by a familial form of Wolff-Parkinson-White syndrome and cardiac hypertrophy. This phenotype is recapitulated in transgenic mice with cardiomyocyte-restricted expression of AMPKgamma(2)R302Q. Although considerable information is known regarding the consequences of harboring the gamma(2)R302Q mutation, little is known about the early signaling events that contribute to the development of this cardiomyopathy.

The AMPK gamma1 R70Q mutant regulates multiple metabolic and growth pathways in neonatal cardiac myocytes.

Although mutations in the gamma-subunit of AMP-activated protein kinase (AMPK) can result in excessive glycogen accumulation and cardiac hypertrophy, the mechanisms by which this occurs have not been well defined. Because >65% of cardiac AMPK activity is associated with the gamma1-subunit of AMPK, we investigated the effects of expression of an AMPK-activating gamma1-subunit mutant (gamma1 R70Q) on regulatory pathways controlling glycogen accumulation and cardiac hypertrophy in neonatal rat cardiac myocytes. Whereas expression of gamma1 R70Q displayed the expected increase in palmitate oxidation rates, rates of glycolysis were significantly depressed.