Cyclin-dependent kinase 6 regulates cardiac embryonic proliferation and pathological hypertrophy.
failure affects 1-3% of people in the Western world and is strongly associated with
cardiac hypertrophy. Studies have linked the cell cycle machinery to this process, but
the role of cyclins and cyclin-dependent kinases (Cdks) remains poorly understood. This
study investigates the role of the G1 cell cycle regulator Cdk6 in normal development
and cardiac stress. Cdk6 acts with... read moreD-type cyclins to promote S-phase entry in
proliferating cells, but is also known to be induced concomitant with cardiac
hypertrophy after transaortic constriction (TAC). Through in vivo studies utilizing Cdk6
knockout (KO) mice, we observed decreased heart weight/tibia length ratios in KO mice
due to reduced embryonic proliferation. No differences in cardiac function at baseline
were observed. In mice subjected to pressure overload, loss of Cdk6 attenuates
pathological cardiac hypertrophy, a physiological response to stress that often leads to
heart failure. Failure to undergo cardiomyocyte hypertrophy along with reductions in
fibrosis and inflammation were observed in response to TAC in KO animals, with
IL-1β and CTGF playing key roles. These data suggest that Cdk6 is an important
regulator of cardiac proliferation during development and of the pathological
hypertrophic response following cardiac
Thesis (Ph.D.)--Tufts University, 2014.
Submitted to the Dept. of Genetics.
Advisors: Philip Hinds, and Gordon Huggins.
Committee: Pamela Yelick, and Grace Gill.
Keywords: Genetics, Cellular biology, and Physiology.read less