Abstract
BackgroundActivation of ErbB2/4 receptor tyrosine kinases in cardiomyocytes by neuregulin treatment is associated with improvement in cardiac function, supporting its use in human patients with heart failure despite the lack of a specific mechanism. Neuregulin infusion in rodents increases cardiac myosin light chain kinase (cMLCK) expression and cardiac myosin regulatory light chain (RLC) phosphorylation which may improve actin-myosin interactions for contraction. We generated a cMLCK knockout mouse to test the hypothesis that cMLCK is necessary for neuregulin-induced improvement in cardiac function by increasing RLC phosphorylation.Principal FindingsThe cMLCK knockout mice have attenuated RLC phosphorylation and decreased cardiac performance measured as fractional shortening. Neuregulin infusion for seven days in wildtype mice increased cardiac cMLCK protein expression and RLC phosphorylation while increasing Akt phosphorylation and decreasing phospholamban phosphorylation. There was no change in fractional shortening. In contrast, neuregulin infusion in cMLCK knockout animals increased cardiac performance in the absence of cMLCK without increasing RLC phosphorylation. In addition, CaMKII signaling appeared to be enhanced in neuregulin-treated knockout mice.ConclusionsThus, Neuregulin may improve cardiac performance in the failing heart without increasing cMLCK and RLC phosphorylation by activating other signaling pathways.
Highlights
Neuregulin is a growth factor which signals to the ErbB family of receptor tyrosine kinases [1]
The reported increase in cardiac myosin light chain kinase expression with increased cardiac myosin regulatory light chain phosphorylation may be a mechanism through which neuregulin treatment increases cardiac performance [7]
Lack of cardiac myosin light chain kinase (cMLCK) and regulatory light chain (RLC) phosphorylation did not lead to significant hypertrophy in adult knockout mice
Summary
Neuregulin is a growth factor which signals to the ErbB family of receptor tyrosine kinases [1]. Cardiac myocytes of the heart express ErbB2/4 receptor tyrosine kinases and neuregulin treatment is associated with several advantageous responses which support its use in human patients with heart failure [2,3,4,5]. Due to the complexity of growth factor signaling, numerous kinases are reported to be activated by neuregulin, and a specific mechanism for the improvement in cardiac function remains elusive [1,5,6]. Activation of ErbB2/4 receptor tyrosine kinases in cardiomyocytes by neuregulin treatment is associated with improvement in cardiac function, supporting its use in human patients with heart failure despite the lack of a specific mechanism. Neuregulin infusion in rodents increases cardiac myosin light chain kinase (cMLCK) expression and cardiac myosin regulatory light chain (RLC) phosphorylation which may improve actin-myosin interactions for contraction. We generated a cMLCK knockout mouse to test the hypothesis that cMLCK is necessary for neuregulin-induced improvement in cardiac function by increasing RLC phosphorylation
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.