Atrial, B-type and C-type natriuretic peptides enhance the sensitivity of bradycardic responses to the cardiogenic chemoreflex (von Bezold-Jarisch reflex) in sheep

Abstract

Certain forms of hypertrophic cardiomyopathy (HCM), are associated with increased activity of the Gq/phospholipase C signaling pathway. To determine the role of Gq signaling in cardiomyopathy at specific times during development, we used the tetracycline transactivator system to conditionally express a mutationally activated form of GOeq (Gq*) in the hearts of transgenic mice. Gq* expression at high levels (3-fold more than wild-type G%) during embryogenesis caused embryonic lethality. Gq* mice survived embryogenesis when Gq* expression was suppressed during that time period. Adult mice (8 weeks old) survived the induction of Gq* expression over a 12-week period. However, adult mice expressing Gq* for over 16 weeks developed marked fibrosis and histopathology consistent with HCM. Force measurements in isolated cardiac muscle strips from mice expressing Gq* for 8 weeks showed a marked reduction in the maximal force of contraction and slowing of the rates of contraction and relaxation. Induction of Gq* expression in adult mice caused decreased basal heart rate and increased heart rate variability. MAP and Jun kinase studies demonstrated increased activity of specific kinase cascades that are thought to be downstream of the Gq signaling pathway. DNA-array analysis of heart tissue from mice with Gq*-induced HCM allowed for identification of over one hundred genes regulated in a distinct pattern from our recently described. Gcinduced model of dilated cardiomyopathy. Functional and genetic characterization of this inducible Gq* model of cardiomyopathy should provide new insights into the genetic cascade leading to HCM and should lead to the identification of new diagnostic markers and potential therapeutic targets.