Protein kinase C (PKC) regulates contractility of myometrium from pregnant women

Abstract

PREGNANT WOMEN VICTOR FOMIN, ANDRIS KRONBERGS, MATTHEW HOFFMAN, University of Delaware, Biological Sciences, Newark, Delaware, Christiana Hospital, Newark, Delaware OBJECTIVE: Prematurity is one of the most significant problems of human pregnancy. According to the March of Dimes, the rate of premature birth increased between 1981 and 2003 by 30% (from 9.4 to 12.3%). A detailed knowledge of the mechanisms of uterine contraction can help to improve clinical control of abnormal uterine function and reverse this trend. Important regulator of smooth muscle contraction is protein kinase C (PKC). However, the role of PKC in uterine (myometrial) contraction remains unclear. This study was designed to investigate an effect of PKC on contraction and intracellular Ca concentration ([Ca]i) in myometrium from term pregnant women. STUDY DESIGN: The myometrial samples were obtained at the time of cesarean section surgery according to the protocol approved by Christiana Hospital and University of Delaware IRB Committees. The isometric contraction (tension) and [Ca]i were measured simultaneously in fura-2 loaded myometrial strips. RESULTS: The PKC activation with phorbol 12,13-dibutyrate (PDBu) increased tonic contraction time and dosedependently reaching maximum after 2hrs at 10 -6M with no effect on [Ca]i. PDBu first potentiated KCl(50mM) contractile responses followed by their inhibition after 1 hr incubation with no effect on the amplitude of the [Ca]i response. PKCalpha inhibitor Go6976 decreased the PDBu effect on the tonic contraction. The depletion of PKCalpha protein with the specific antisense oligonucleotide decreased the KCl-induced contractile and [Ca]i responses. CONCLUSION: It is suggested that PKC regulates uterine contraction through different signaling pathways. First, PKC (possibly PKCalpha) stimulates KCl-induced contractile responses followed by their inhibition due to yet to be determined mechanisms. PKC also induces myometrial tonic contraction without changes in [Ca]i. (Supported by NIH R55 HD45802).