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.