Cardiac specific overexpression of transglutaminase II (G(h)) results in a unique hypertrophy phenotype independent of phospholipase C activation.
Tissue type transglutaminase (TGII, also known as G(h)) has been considered a multifunctional protein, with both transglutaminase and GTPase activity. The role of the latter function, which is proposed as a coupling mechanism between alpha(1)-adrenergic receptors and phospholipase C (PLC), is not well defined. TGII was overexpressed in transgenic mice in a cardiac specific manner to delineated relevant signaling pathways and their consequences in the heart. Cardiac transglutaminase activity in the highest expressing line was approximately 37-fold greater than in nontransgenic lines. However, in vivo signaling to PLC, as assessed by inositol phosphate turnover in [(3)H]myoinositol organ bath atrial preparations, was not increased in the TGII mice at base line or in response to alpha(1)-adrenergic receptor stimulation; nor was protein kinase Calpha (PKCalpha) or PKCepsilon activity enhanced in the TGII transgenic mice. This is in contrast to mice moderately (approximately 5-fold) overexpressing G(alphaq), where inositol phosphate turnover and PKC activity were found to be clearly enhanced. TGII overexpression resulted in a remodeling of the heart with mild hypertrophy, elevated expression of beta-myosin heavy chain and alpha-skeletal actin genes, and diffuse interstitial fibrosis. Resting ventricular function was depressed, but responsiveness to beta-agonist was not impaired. This set of pathophysiologic findings is distinct from that evoked by overexpression of G(alphaq). We conclude that TGII acts in the heart primarily as a transglutaminase, and modulation of this function results in unique pathologic sequelae. Evidence for TGII acting as a G-protein-like transducer of receptor signaling to PLC in the heart is not supported by these studies.
Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
K
K
Small
J F
JF
Feng
J
J
Lorenz
E T
ET
Donnelly
A
A
Yu
M J
MJ
Im
G W
GW
Dorn
S B
SB
Liggett
D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics*; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000096:biosynthesis / Q000235:genetics*; D019204:GTP-Binding Proteins; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D008822:Mice, Transgenic; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D015398:Signal Transduction; D011503:Transglutaminases / Q000096:biosynthesis / Q000235:genetics*; D010738:Type C Phospholipases / Q000235:genetics* / Q000378:metabolism
D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D010738:Type C Phospholipases; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins