Regulation of cardiac fatty acids metabolism in transgenic mice overexpressing bovine GH

Abstract

Cardiac energy metabolism depends mainly on fatty acid (FA) oxidation; however, regulation of FA metabolism in acromegalic (Acro) heart is unknown. The aim of the study was to evaluate cardiac expression of key proteins of FA metabolism in young and elder transgenic mice overexpressing bovine GH Acro. Expression of proteins regulating FA entry into the cells, their uptake by mitochondria and beta-oxidation were evaluated by western blot, while FA content by Fourier transform infrared microspectrometry. Regulatory mechanisms of key steps of FA metabolism were also studied. The expression of plasma-membrane FA carriers (fatty acid-binding protein and fatty acid transport protein-1) and acylCoA synthetase was higher in young and lower in elder Acro than in corresponding controls; likewise, expression of cytoplasm to mitochondria-1 (CPT-1), the key enzyme of mitochondrial FA uptake, and that of medium-chain acyl-CoA dehydrogenase and long-chain acyl-CoA dehydrogenase, two regulatory beta-oxidation dehydrogenases, followed a similar pattern. FA content was lower in young and higher in elder Acro than in wild-type, suggesting an increased utilisation in young animals. GH regulated expression of key proteins of FA metabolism through changes in peroxisome proliferator-activated receptor alpha (PPARalpha) expression, which varied accordingly. GH effect was confirmed by treatment of Acro mice with a receptor antagonist, which abolished changes in key proteins of FA metabolism in young Acro. GH increased phosphorylation of AMP-activated protein kinase and anti-acetyl-CoA-carboxylase, two regulatory kinases, leading to lower CPT-1 inhibition by malonyl-CoA, and intervened in regulating PPARalpha expression through the ERK 1/2 pathway. In conclusion, chronic GH excess increased FA metabolism in the young age, whereas its action was overwhelmed in elder ages likely by GH-independent mechanisms, leading to reduced expression of key enzyme of FA metabolism.

Cardiac extrinsic apoptotic pathway is silent in young but activated in elder mice overexpressing bovine GH: interplay with the intrinsic pathway

“…In conclusion, our data demonstrated the activation of the extrinsic pathway of cardiac apoptosis in elder acromegalic animals, which are characterized by ventricular hypertrophy (Bohlooly-Y et al 2001) and abnormalities of energetic (Bohlooly-Y et al 2001, Bogazzi et al 2007) and lipid (Bogazzi et al 2009b) metabolism. Interestingly, those changes may, at least partially, revert in young Acro animals during pegvisomant therapy, supporting the concept that changes in energetic metabolism and apoptosis degree might have different impacts on the cardiac function of young and elder animals.…”

“…1 mg/daily, s.c. for 15 days) as previously reported (Liao et al 2006, Bogazzi et al 2008, 2009b. To exclude any antagonist's proper effect, Wt animals were treated with pegvisomant; in addition, Wt and Acro animals were also treated with vehicle.…”

“…To exclude any antagonist's proper effect, Wt animals were treated with pegvisomant; in addition, Wt and Acro animals were also treated with vehicle. Treatment with pegvisomant (or vehicle) lasted 15 days owing to the rapid effect of pegvisomant and for a better comparison with our previous studies on cardiac apoptosis (Bogazzi et al 2007(Bogazzi et al , 2008(Bogazzi et al , 2009b. Effectiveness of pegvisomant was evaluated by measuring serum IGF1 concentrations before and at the end of treatment.…”

“…Serum IGF1 concentrations were measured using a commercial kit (Diagnostic System Laboratories, Webster, TX, USA), as previously reported (Bogazzi et al 2008(Bogazzi et al , 2009b.…”

Aliskiren affects fatty-acid uptake and lipid-related genes in rodent and human cardiomyocytes

“…In our cardiomyocytes, aliskiren did not decrease expression of (P)Rr or Igf2/M6Pr receptors, so the angiotensin II-independent effects of a potential renin increase at the cardiac level should perhaps be further considered in relation to clinical treatment. It has also recently been demonstrated that the ERK1/2 pathway activation is involved in regulating cardiac fatty-acid metabolism [82] and in the contraction-induced increase in plasma-membrane CD-36…”