Sarcomeric dysfunction in heart failure.
Sarcomeric dysfunction plays a central role in reduced cardiac pump function in heart failure. This review focuses on the alterations in sarcomeric proteins in diseased myocardium that range from altered isoform expression to post-translational protein changes such as proteolysis and phosphorylation. Recent studies in animal models of heart failure and human failing myocardium converge and indicate that sarcomeric dysfunction, including altered maximum force development, Ca(2+) sensitivity, and increased passive stiffness, largely originates from altered protein phosphorylation, caused by neurohumoral-induced alterations in the kinase-phosphatase balance inside the cardiomyocytes. Novel therapies, which specifically target phosphorylation sites within sarcomeric proteins or the kinases and phosphatases involved, might improve cardiac function in heart failure.
Hamdani
Nazha
N
Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, van der Boechorststraat 7, Amsterdam, The Netherlands.
Kooij
Viola
V
van Dijk
Sabine
S
Merkus
Daphne
D
Paulus
Walter J
WJ
Remedios
Cris Dos
CD
Duncker
Dirk J
DJ
Stienen
Ger J M
GJ
van der Velden
Jolanda
J
D000818:Animals; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D009124:Muscle Proteins / Q000378:metabolism*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012518:Sarcomeres / Q000378:metabolism* / Q000473:pathology
D009124:Muscle Proteins; D020033:Protein Isoforms; D011494:Protein Kinases; D010447:Peptide Hydrolases