DOCK10 is vital for normal cardiac function under neurohormonal activation

L. Segal, Sharon Etzion, Sigal Elyagon, M. Numa, A. Livitas, E. Muhammad, Madison Kapiloff, R. Parvari, Yoram Etzion

Research output: Contribution to journalMeeting Abstract

Abstract

Background: Dock10 is a guanine nucleotide exchange factor of Cdc42 and Rac1. These Rho family kinases are known to have important regulatory roles in the heart. Unpublished data from our group recently identified a possible link between a mutation in a highly conserved region of Dock10 and an autosomal recessive form of severe dilated cardiomyopathy.

We hypothesize that Dock10 serves as a critical regulator of cardiac signal transduction. In this study we characterized the phenotype of mice with global Dock10 knockout (KO).

Methods and results: Mice homozygous for a Dock10 knock-out first allele (EM:04723) were compared to littermate controls. Gravimetric analysis (heart weight to body weight ratio) and echocardiography were performed at baseline and following two weeks of exposure to Angiotensin II (Ang II, 2 mg/kg/day). Contractility and calcium handling of isolate cardiomyocytes were evaluated using an IonOptix system.

Mice with global Dock10 KO had normal body weight and cardiac size at 3 month of age. However, echocardiography revealed reduced fractional shortening and IonOptix recordings demonstrated reduced contractility and elevated diastolic calcium in isolated KO cardiomyocytes. Exposure to Ang II markedly elevated the expression of Dock10 in the heart tissue of wild-type mice. Dock10 KO mice had increased heart weight to body weight ratio, elevated fibrosis and markedly reduced systolic function following Ang II treatment.

Conclusion: Our data suggest that Dock10 is vital for normal cardiac function particularly under neurohormonal activation. Further work is needed to understand the mechanism\s of action of Dock10 in the normal and failing heart
Original languageEnglish
Pages (from-to)18
JournalJournal of Molecular and Cellular Cardiology
Volume120
DOIs
StatePublished - 1 Jul 2018

Fingerprint

Dive into the research topics of 'DOCK10 is vital for normal cardiac function under neurohormonal activation'. Together they form a unique fingerprint.

Cite this