Identifying cellular mechanisms of zinc-induced relaxation in isolated cardiomyocytes
| Autor: | Ting-Ting Yi, Jonathan S. Vick, Bradley M. Palmer, Kelly J. Begin, Marc J H Vecchio, Rona J. Delay, Stephen P. Bell |
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| Rok vydání: | 2013 |
| Předmět: |
inorganic chemicals
Male Sarcomeres medicine.medical_specialty Patch-Clamp Techniques Calcium Channels L-Type Physiology Muscle Relaxation chemistry.chemical_element Zinc Rats Inbred WKY Sarcomere Sarcoplasmic Reticulum Calcium-Transporting ATPases Rats Sprague-Dawley Mice Physiology (medical) Internal medicine medicine Animals Myocyte Myocytes Cardiac Diastolic function Dose-Response Relationship Drug Cardiac Excitation and Contraction Chemistry Ryanodine receptor Ryanodine Receptor Calcium Release Channel Rats Mice Inbred C57BL Endocrinology Models Animal Biophysics Relaxation (physics) Calcium Cardiology and Cardiovascular Medicine |
| Zdroj: | American Journal of Physiology-Heart and Circulatory Physiology. 305:H706-H715 |
| ISSN: | 1522-1539 0363-6135 |
| DOI: | 10.1152/ajpheart.00025.2013 |
| Popis: | We tested several molecular and cellular mechanisms of cardiomyocyte contraction-relaxation function that could account for the reduced systolic and enhanced diastolic function observed with exposure to extracellular Zn2+. Contraction-relaxation function was monitored in isolated rat and mouse cardiomyocytes maintained at 37°C, stimulated at 2 or 6 Hz, and exposed to 32 μM Zn2+ or vehicle. Intracellular Zn2+ detected using FluoZin-3 rose to a concentration of ∼13 nM in 3–5 min. Peak sarcomere shortening was significantly reduced and diastolic sarcomere length was elongated after Zn2+ exposure. Peak intracellular Ca2+ detected by Fura-2FF was reduced after Zn2+ exposure. However, the rate of cytosolic Ca2+ decline reflecting sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a) activity and the rate of Na+/Ca2+ exchanger activity evaluated by rapid Na+-induced Ca2+ efflux were unchanged by Zn2+ exposure. SR Ca2+ load evaluated by rapid caffeine exposure was reduced by ∼50%, and L-type calcium channel inward current measured by whole cell patch clamp was reduced by ∼70% in cardiomyocytes exposed to Zn2+. Furthermore, ryanodine receptor (RyR) S2808 and phospholamban (PLB) S16/T17 were markedly dephosphorylated after perfusing hearts with 50 μM Zn2+. Maximum tension development and thin-filament Ca2+ sensitivity in chemically skinned cardiac muscle strips were not affected by Zn2+ exposure. These findings suggest that Zn2+ suppresses cardiomyocyte systolic function and enhances relaxation function by lowering systolic and diastolic intracellular Ca2+ concentrations due to a combination of competitive inhibition of Ca2+ influx through the L-type calcium channel, reduction of SR Ca2+ load resulting from phospholamban dephosphorylation, and lowered SR Ca2+ leak via RyR dephosphorylation. The use of the low-Ca2+-affinity Fura-2FF likely prevented the detection of changes in diastolic Ca2+ and SERCA2a function. Other strategies to detect diastolic Ca2+ in the presence of Zn2+ are essential for future work. |
| Databáze: | OpenAIRE |
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