Ca2+ sparks in heart have been shown by the PI to occur under physiological conditions during diastole and systole. They not only underlie the normal [Ca2+]i transient but have been found to be critically important in mediating the cellular response to stress and disease, contributing to contractile and arrhythmic dysfunction in conditions ranging from calcium overload to the cardiomyopathy of muscular dystrophy. Recently, work by the PI shows that physiologic stretch, such as that experienced by a myocyte during diastolic filling, dramatically alters Ca2+ spark occurrence transiently in normal cardiac ventricular myocytes. This behavior depends on microtubules affecting the release mechanisms of the sarcoplasmic reticulum (SR). Despite the importance of this new discovery one year ago, we have only now developed the additional tools needed to investigate how dynamic length changes can affect the triggering of Ca2+ sparks under diverse conditions. Using these new tools, we observe (in preliminary investigations) that stretch-dependent changes in Ca2+ sparks are even larger than previously observed and appear to arise from a transient increase in the the sensitivity of ryanodine receptors (RyR2s). Additional preliminary work shows that, surprisingly, this transient increase in Ca2+ sparks underlies the activation of arrhythmogenic Ca2+ waves at a very low rate in heart cells from control mice, but at a much higher rate in myocytes from mdx mice, the murine model of Duchenne muscular dystrophy, or from control mice with excessive calcium in the SR. The tools developed by the PI and his colleagues will enable an innovative state-of-the-art investigation into how cardiac Ca2+ signaling is modulated by physiological stretch. The proposed work seeks to investigate stretch-dependent Ca2+ sparks and Ca2+ waves in 1. control ventricular myocytes;2. ventricular myocytes in which RyR2 properties have been altered;3. ventricular myocytes when microtubules are modulated;4. ventricular myocytes from dystrophin null (mdx) mice. The planned research should reveal for the first time the importance of stretch in normal and pathological Ca2+ signaling of cardiac ventricular myocytes. The work will therefore provide not only fundamental new information on normal cellular behavior but also on mechanisms of arrhythmogenesis. Furthermore it will lay the foundation for novel therapies for diverse heart diseases including Duchenne muscular dystrophy.

Public Health Relevance

Contraction and the heart rhythm are regulated by calcium inside of heart cells. This calcium level is now known to be set in part by changes in the cell length (these changes are also called stretch), a surprising result that was discovered recently by the scientists working on this proposal. The planned work will examine such stretch-dependent changes in cellular calcium and function and determine how stretch underlies normal and defective heart function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL106059-02
Application #
8204669
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Lathrop, David A
Project Start
2011-01-01
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$375,000
Indirect Cost
$125,000
Name
University of Maryland Baltimore
Department
Physiology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Greiser, Maura; Kerfant, BenoƮt-Gilles; Williams, George S B et al. (2014) Tachycardia-induced silencing of subcellular Ca2+ signaling in atrial myocytes. J Clin Invest 124:4759-72
Ward, Christopher W; Prosser, Benjamin L; Lederer, W Jonathan (2014) Mechanical stretch-induced activation of ROS/RNS signaling in striated muscle. Antioxid Redox Signal 20:929-36
Mannella, Carmen A; Lederer, W Jonathan; Jafri, M Saleet (2013) The connection between inner membrane topology and mitochondrial function. J Mol Cell Cardiol 62:51-7
Boyman, Liron; Williams, George S B; Khananshvili, Daniel et al. (2013) NCLX: the mitochondrial sodium calcium exchanger. J Mol Cell Cardiol 59:205-13
Williams, George S B; Boyman, Liron; Chikando, Aristide C et al. (2013) Mitochondrial calcium uptake. Proc Natl Acad Sci U S A 110:10479-86
Prosser, Benjamin L; Ward, Christopher W; Lederer, W Jonathan (2013) X-ROS signalling is enhanced and graded by cyclic cardiomyocyte stretch. Cardiovasc Res 98:307-14
Sobie, Eric A; Lederer, W J (2012) Dynamic local changes in sarcoplasmic reticulum calcium: physiological and pathophysiological roles. J Mol Cell Cardiol 52:304-11
Brochet, Didier X P; Yang, Dongmei; Cheng, Heping et al. (2012) Elementary calcium release events from the sarcoplasmic reticulum in the heart. Adv Exp Med Biol 740:499-509
Liu, Ona Z; Lederer, W J; Sobie, Eric A (2012) Does the Goldilocks Principle apply to calcium release restitution in heart cells? J Mol Cell Cardiol 52:3-6

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