Frequency‐dependent myofilament Ca2+ desensitization in failing rat myocardium
- 5 July 2007
- journal article
- Published by Wiley in The Journal of Physiology
- Vol. 582 (2), 695-709
- https://doi.org/10.1113/jphysiol.2007.134486
Abstract
The positive force-frequency relation, one of the key factors modulating performance of healthy myocardium, has been attributed to an increased Ca(2+) influx per unit of time. In failing hearts, a blunted, flat or negative force-frequency relation has been found. In healthy and failing hearts frequency-dependent alterations in Ca(2+) sensitivity of the myofilaments, related to different phosphorylation levels of contractile proteins, could contribute to this process. Therefore, the frequency dependency of force, intracellular free Ca(2+) ([Ca(2+)](i)), Ca(2+) sensitivity and contractile protein phosphorylation were determined in control and monocrotaline-treated, failing rat hearts. An increase in frequency from 0.5 to 6 Hz resulted in an increase in force in control (14.3 +/- 3.0 mN mm(-2)) and a decrease in force in failing trabeculae (9.4 +/- 3.2 mN mm(-2)), whereas in both groups the amplitude of [Ca(2+)](i) transient increased. In permeabilized cardiomyocytes, isolated from control hearts paced at 0 and 9 Hz, Ca(2+) sensitivity remained constant with frequency (pCa(50): 5.55 +/- 0.02 and 5.58 +/- 0.01, respectively, P>0.05), whereas in cardiomyocytes from failing hearts Ca(2+) sensitivity decreased with frequency (pCa(50): 5.62 +/- 0.01 and 5.57 +/- 0.01, respectively, P<0.05). After incubation of the cardiomyocytes with protein kinase A (PKA) this frequency dependency of Ca(2+) sensitivity was abolished. Troponin I (TnI) and myosin light chain 2 (MLC2) phosphorylation remained constant in control hearts but both increased with frequency in failing hearts. In conclusion, in heart failure frequency-dependent myofilament Ca(2+) desensitization, through increased TnI phosphorylation, contributes to the negative force-frequency relation and is counteracted by a frequency-dependent MLC2 phosphorylation. We propose a novel role for PKC-mediated TnI phosphorylation in modulating the force-frequency relation.Keywords
This publication has 57 references indexed in Scilit:
- Heart failure-associated alterations in troponin I phosphorylation impair ventricular relaxation-afterload and force-frequency responses and systolic functionAmerican Journal of Physiology-Heart and Circulatory Physiology, 2007
- Acceleration of Stretch Activation in Murine Myocardium due to Phosphorylation of Myosin Regulatory Light ChainThe Journal of general physiology, 2006
- Hypertrophic Cardiomyopathy in Cardiac Myosin Binding Protein-C Knockout MiceCirculation Research, 2002
- Myofilament properties comprise the rate-limiting step for cardiac relaxation at body temperature in the ratAmerican Journal of Physiology-Heart and Circulatory Physiology, 2002
- Beneficial effects of the Ca2+sensitizer levosimendan in human myocardiumAmerican Journal of Physiology-Heart and Circulatory Physiology, 2002
- Effects of Calcium, Inorganic Phosphate, and pH on Isometric Force in Single Skinned Cardiomyocytes From Donor and Failing Human HeartsCirculation, 2001
- The Cardiac β -Adrenoceptor-G-protein(s)-adenylyl Cyclase System in Monocrotaline-treated RatsJournal of Molecular and Cellular Cardiology, 2000
- Chamber-specific alterations of noradrenaline uptake (uptake1 ) in right ventricles of monocrotaline-treated ratsBritish Journal of Pharmacology, 2000
- Levosimendan improves diastolic and systolic function in failing human myocardiumEuropean Journal of Pharmacology, 2000
- Isometric tension development and its calcium sensitivity in skinned myocyte-sized preparations from different regions of the human heartCardiovascular Research, 1999