Upregulation of Phospholipase D Expression and Activation in Ventricular Pressure-Overload Hypertrophy

Abstract

Abstract. Evidence for a role of phospholipase D (PLD) in cellular proliferation and differentiation is accumulating. We studied PLD activity and expression in normal and hypertrophic rat and human hearts. In rat heart, abdominal aortic banding (constriction to 50% of original lumen) caused hypertrophy in the left ventricle (as shown by weight index and ANP expression) by about 15% after 30 days without histological evidence of fibrosis or signs of decompensation and in the right ventricle after 100 days. The hypertrophy was accompanied by small increases of basal PLD activity and strong potentiation of stimulated PLD activity caused by 4β-phorbol-12β,13α-dibutyrate (PDB) and by phenylephrine. The mRNA expressions of both PLD1 and PLD2 determined by semiquantitative competitive RT-PCR were markedly enhanced after aortic banding. In the caveolar fraction of the rat heart, PLD2 protein determined by Western blot analysis was upregulated in parallel with the expression of caveolin-3. A similar induction of PLD mRNA and protein expression was observed in hypertrophied human hearts of individuals (39 -45-year-old) who had died from non-cardiac causes. In conclusion, PLD1 and PLD2 expressions were strongly enhanced both in rat and human heart hypertrophy, which may be responsible for the coincident potentiation of the PLD activation by α-adrenoceptor and protein kinase C stimulation. These results are compatible with a significant role of PLD activation in cell signaling of ventricular pressure-overload hypertrophy.

Exchange Protein Directly Activated by cAMP (epac): A Multidomain cAMP Mediator in the Regulation of Diverse Biological Functions

“…To add even more complexity, earlier studies report that the PLD product phosphatidic acid activates PDE4D3 (Grange et al, 2000) and that PLD expression is upregulated in response to ventricular pressureoverload hypertrophy (Peivandi et al, 2005). These findings implicate that alterations in activity and/or expression of factors that are part of cAMP-sensing multiprotein complexes, such as PDE4D3 (DodgeKafka et al, 2005), or factors that determine the subcellular localization of Epac, such as phosphatidic acid (Consonni et al, 2012), exhibit different signaling properties and therefore alter the ability of Epac to act either anti-and/or pro-hypertrophic in the heart.…”

Involvement of lipid rafts and caveolae in cardiac ion channel function

“…Recent studies showed that statin therapy affects caveolar turnover by limiting their endocytosis [128]. Atorvastatin has also been shown to modulate the cholesterol enrichment of the lipid rafts [129].…”

Phospholipid-mediated signaling in diseased myocardium

“…Fas receptor activation is an important component in hypertrophy induced by pressure-and volume-overload and recently it has been reported that Fas-mediated hypertrophy is dependent upon the IP 3 pathway, which is functionally interconnected to the phosphoinositide-3 kinase/AKT/glycogen synthase kinase-3β pathway; both pathways act in concert to cause nuclear factor of activated T cells nuclear translocation and subsequent hypertrophy [130]. Recent evidence suggests that ventricular pressure overload hypertrophy led to an upregulation of PLD isozymes both in rat and human heart, which may be due to potentiation of PLD activation by α-adrenoceptor and PKC stimulation [131]. PA produced by the activation of PLD also stimulates SL PLC activity [56,132].…”