Mixed Lineage Kinase 3 (MLK3) functions as a cGMP-dependent protein kinase I alpha (PKGI) substrate and inhibits cardiac remodeling in vivo
kinase G I (PKGI) prevents cardiac hypertrophy and dysfunction in the failing heart.
Although PKGI-activating drugs remain under investigation for the treatment of heart
failure, the downstream molecular substrates through which PKGI regulates these
processes remain incompletely understood. In this study we identified one candidate
PKGIα substrate in the myocardium, Mixed ... read moreLineage Kinase 3, (MLK3) an upstream
regulator of stress-responsive JNK signaling. We first tested for a PKGIα-MLK3
protein-protein interaction with endogenous proteins in the myocardium by
co-immunoprecipitation. We confirmed direct PKGIα-MLK3 interaction with affinity
purified proteins. In cultured cardiac myocytes MLK3 mediated cGMP-stimulated JNK
phosphorylation, and pharmacologic inhibition of MLK3 kinase activity induced
cardiomyocyte hypertrophy. MLK3 protein expression increased in myocardial tissues from
humans with end-stage heart failure and cardiac remodeling. Mice with genetic deletion
of MLK3 (MLK3-/-) exhibited baseline cardiac hypertrophy with preserved cardiac function
and structure. In response to pressure overload, MLK3-/- mice had worsened cardiac
function and increased cardiomyocyte hypertrophy. Together these data demonstrate MLK3
is a novel PKGIα substrate, indicate MLK3 functions as a cardioprotective
molecule, and further support the approach of exploring myocardial
PKGIα-substrates to identify novel anti-remodeling
Thesis (M.S.)--Tufts University, 2017.
Submitted to the Dept. of Clinical & Translational Science.
Advisor: Gordon Huggins.
Committee: Richard Karas, and Farzad Noubary.
Keywords: Molecular biology, Physiology, and Biology.read less