Handling the Pressure
Cardiac hypertrophy, or thickening of the heart muscle, develops in response to an increase in cardiac pressure associated with several forms of heart disease including hypertension, heart failure and loss of arterial elasticity. Progression of hypertrophy requires many cellular process including protein synthesis and degradation, as well as changes in cardiac metabolism. It is unclear how these different processes are coordinated. Jonathan Schisler and colleagues at the McAllister Heart Institute show that the protein quality regulator protein, C terminus of HSC70-interacting protein (CHIP), acts as a chaperone for AMPK activation by promoting its phosphorylation by LKB1 kinase in response to cardiac stress. In the absence of CHIP, mice had decreased cardiac function, increased hypertrophy and a reduction in energy generation in response to cardiac pressure. This study establishes a link between cardiac proteolytic and metabolic pathways. The above image is a false-colored electronmicrograph of a transverse section though a heart isolated from a Chip-/- mouse after one week of pressure overload. Large lipid droplets are blue, dense muscle fibers are red, and the extracellular matrix is colored green
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Abstract
Protein quality control and metabolic homeostasis are integral to maintaining cardiac function during stress; however, little is known about if or how these systems interact. Here we demonstrate that C terminus of HSC70-interacting protein (CHIP), a regulator of protein quality control, influences the metabolic response to pressure overload by direct regulation of the catalytic α subunit of AMPK. Induction of cardiac pressure overload in
Authors
Jonathan C. Schisler, Carrie E. Rubel, Chunlian Zhang, Pamela Lockyer, Douglas M. Cyr, Cam Patterson
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