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(Circulation Research. 2009;104:12.)
© 2009 American Heart Association, Inc.

Editorials

Transcriptional and Posttranslational Modifications of Titin

Implications for Diastole

Attila Borbély, Loek van Heerebeek, Walter J. Paulus

From the Institute of Cardiology (A.B.), University of Debrecen Medical and Health Science Center, Hungary; and the Department of Physiology (A.B., L.v.H., W.P.), Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center Amsterdam, The Netherlands.

Correspondence to Prof Dr Walter J. Paulus, MD, PhD, Department of Physiology, VU University Medical Center Amsterdam, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. E-mail wj.paulus@vumc.nl

See related article, pages 87–94

Key Words: diastole • titin • myocardium • heart failure • myofilaments

An extract of the first 250 words of the full text is provided, because this article has no abstract.

	Introduction

 
Myocardial diastolic stiffness has been variably attributed to extracellular matrix composition, cytoskeletal properties of cardiomyocytes, or residual diastolic crossbridge cycling because of incomplete relaxation or cytosolic calcium removal.¹ Extracellular matrix and cardiomyocyte cytoskeleton are presumed to mediate chronic rises in myocardial diastolic stiffness, as occur during aging, pressure overload or heart failure, whereas residual diastolic crossbridge cycling accounts for acute changes, as observed during ischemia, exercise, or pharmacological interventions. The elegant study by Krüger et al, published in this issue of Circulation Research, challenges this conceptual framework.² The study demonstrates that protein kinase (PK)G is capable of phosphorylating the giant cytoskeletal protein titin, as previously reported for PKA^3,4 and that phosphorylation by PKG or PKA of a serine residue within the N2B fragment of titin leads to an acute fall in cardiomyofibrillar stiffness. An acute effect produced by a cytoskeletal protein invalidates the concept of distinct mediators for chronic or acute changes in myocardial diastolic stiffness. From these and other recent observations it becomes evident that the cytoskeletal protein titin can alter myocardial diastolic stiffness, both acutely and chronically, through multiple mechanisms such as isoform shifts, phosphorylation by PKG or PKA, and titin–actin interaction at the Z-disc (Figure).

View larger version (19K):   Figure. Titin alters cardiomyocyte stiffness through isoform shifts, phosphorylation, and titin–actin interaction. A, Sarcomeric structure with detailed view of I-band region of N2B titin isoform showing tandem immunoglobulin (Ig), N2B, and elastic PEVK segments. B through D, Shift from N2B to N2BA titin isoform (B) and phosphorylation by PKG . . . [Full Text of this Article]

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