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(Circulation Research. 2007;101:975.)
© 2007 American Heart Association, Inc.

Review

Endoplasmic Reticulum Stress in the Heart

Christopher C. Glembotski

From the San Diego State University Heart Institute and the Department of Biology, San Diego State University, Calif.

Correspondence to Christopher C. Glembotski, SDSU Heart Institute and the Department of Biology, San Diego State University, 5500 Campanile Dr, San Diego, CA 92182. E-mail cglembotski{at}sciences.sdsu.edu

Over the last decade, it has become clear that the accumulation of misfolded proteins contributes to a number of neurodegenerative, immune, and endocrine pathologies, as well as other age-related illnesses. Recent interest has focused on the possibility that the accumulation of misfolded proteins can also contribute to vascular and cardiac diseases. In large part, the misfolding of proteins takes place during synthesis on free ribosomes in the cytoplasm or on endoplasmic reticulum ribosomes. In fact, even under optimal conditions, 30% of all newly synthesized proteins are rapidly degraded, most likely because of improper folding. Accordingly, stresses that perturb the folding of proteins during or soon after synthesis can lead to the accumulation of misfolded proteins and to potential cellular dysfunction and pathological consequences. To avert such outcomes, cells have developed elaborate protein quality-control systems for detecting misfolded proteins and making appropriate adjustments to the machinery responsible for protein synthesis and/or degradation. Important contributors to protein quality control include cytosolic and organelle-targeted molecular chaperones, which help fold and stabilize proteins from unfolding, and the ubiquitin proteasome system, which degrades terminally misfolded proteins. Both of these systems play important roles in cardiovascular biology. The focus of this review is the endoplasmic reticulum stress response, a protein quality-control and signal-transduction system that has not been well studied in the context of cardiovascular biology but that could be important for vascular and cardiac health and disease.

Key Words: ATF6 • ER stress • ischemia • unfolded protein response • XBP1

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