• Determining the Molecular Basis for Depressed Ventricular Contractile Function in Cardiac Neural Creat-Ablated Chick Embryos

      Hatcher, Cathy J; Department of Biochemistry and Molecular Biology (1998-01)
      Ablation of the cardiac neural crest (CNC A) in embryonic chicks at Hamburger- Hamilton stages 8-10 results in a high incidence of persistent truncus arteriosus, a congenital heart defect characterized by a single arterial trunk leaving the heart. Decreased ventricular contractility, which could be due to defects at the level of the contractile apparatus or in the excitation-contraction coupling (ECC) process, has been documented in this model. The first hypothesis that the decrease in isometric force produced per cross-bridge by Triton-skinned ventricular muscle preparations was due to inhibition of the contractile apparatus caused by excessive microtubules was not supported by the data: (1) The total microtubule content and the maximum calcium-activated forc generated by ventricular muscle strips of hearts from embryonic day (ED) 15 CNC A and sham-operated control embryos was not significantly different. (2) Destabilization of microtubules in ventricular muscle strips did not improve the force-producing capability of the contractile apparatus in CNCA embryos. Therefore, microtubules do not appear to be the cause for decreased isometric force production. The second hypothesis that the decrease in ventricular contractility was due to an improperly functioning FKBP1 2 .6 , a ryanodine receptor (RyR) modulatory protein which plays a role in ECC, was supported by the data: (1) FKBP1 2 .6 was present in comparable amounts in hearts from ED 15 CNCA and sham-operated embryos, (2) Dissociation of FKBP1 2 .6 from the RyR had significant effects on intact twitch force and calcium-induced calcium release from the sarcoplasmic reticulum in ED IS sham-operated, but not CNCA embryos. Therefore, FKBP1 2 .6 is present, but not functional in hearts from CNCA embryos, and, thereby, plays a major role in the impaired ECC in these hearts.