Phospholipase C epsilon modulates beta-adrenergic receptor-dependent cardiac contraction and inhibits cardiac hypertrophy.
Phospholipase C (PLC) epsilon is a recently identified enzyme regulated by a wide range of molecules including Ras family small GTPases, Rho A, Galpha(12/13), and Gbetagamma with primary sites of expression in the heart and lung. In a screen for human signal transduction genes altered during heart failure, we found that PLCepsilon mRNA is upregulated. Two murine models of cardiac hypertrophy confirmed upregulation of PLCepsilon protein expression or PLCepsilon RNA. To identify a role for PLCepsilon in cardiac function and pathology, a PLCepsilon-deficient mouse strain was created. Echocardiography indicated PLCepsilon(-/-) mice had decreased cardiac function, and direct measurements of left ventricular contraction demonstrated that PLCepsilon(-/-) mice had a decreased contractile response to acute isoproterenol administration. Cardiac myocytes isolated from PLCepsilon(-/-) mice had decreased beta-adrenergic receptor (betaAR)-dependent increases in Ca2+ transient amplitudes, likely accounting for the contractile deficiency in vivo. This defect appears to be independent from the ability of the betaAR system to produce cAMP and regulation of sarcoplasmic reticulum Ca2+ pool size. To address the significance of these functional deficits to cardiac pathology, PLCepsilon(-/-) mice were subjected to a chronic isoproterenol model of hypertrophic stress. PLCepsilon(-/-) mice were more susceptible than wild-type littermates to development of hypertrophy than wild-type littermates. Together, these data suggest a novel PLC-dependent component of betaAR signaling in cardiac myocytes responsible for maintenance of maximal contractile reserve and loss of PLCepsilon signaling sensitizes the heart to development of hypertrophy in response to chronic cardiac stress.
Wang
Huan
H
Department of Pharmacology and Physiology, University of Rochester School of Medicine, Rochester, NY 14642, USA.
Oestreich
Emily A
EA
Maekawa
Naoya
N
Bullard
Tara A
TA
Vikstrom
Karen L
KL
Dirksen
Robert T
RT
Kelley
Grant G
GG
Blaxall
Burns C
BC
Smrcka
Alan V
AV
D000818:Animals; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology / Q000517:prevention & control*; D006333:Heart Failure / Q000201:enzymology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism; D054801:Phosphoinositide Phospholipase C; D012333:RNA, Messenger / Q000032:analysis; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D010738:Type C Phospholipases / Q000235:genetics / Q000502:physiology*
D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D010738:Type C Phospholipases; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon; D007545:Isoproterenol; D002118:Calcium