Mechanisms of [Ca2+]i transient decrease in cardiomyopathy of db/db type 2 diabetic mice.
Cardiovascular disease is the leading cause of death in the diabetic population. However, molecular mechanisms underlying diabetic cardiomyopathy remain unclear. We analyzed Ca2+-induced Ca2+ release and excitation-contraction coupling in db/db obese type 2 diabetic mice and their control littermates. Echocardiography showed a systolic dysfunction in db/db mice. Two-photon microscopy identified intracellular calcium concentration ([Ca2+]i) transient decrease in cardiomyocytes within the whole heart, which was also found in isolated myocytes by confocal microscopy. Global [Ca2+]i transients are constituted of individual Ca2+ sparks. Ca2+ sparks in db/db cardiomyocytes were less frequent than in +/+ myocytes, partly because of a depression in sarcoplasmic reticulum Ca2+ load but also because of a reduced expression of ryanodine receptor Ca2+ channels (RyRs), revealed by [3H]ryanodine binding assay. Ca2+ efflux through Na+/Ca2+ exchanger was increased in db/db myocytes. Calcium current, I(Ca), triggers sarcoplasmic reticulum Ca2+ release and is also involved in sarcoplasmic reticulum Ca2+ refilling. Macroscopic I(Ca) was reduced in db/db cells, but single Ca2+ channel activity was similar, suggesting that diabetic myocytes express fewer functional Ca2+ channels, which was confirmed by Western blots. These results demonstrate that db/db mice show depressed cardiac function, at least in part, because of a general reduction in the membrane permeability to Ca2+. As less Ca2+ enters the cell through I(Ca), less Ca2+ is released through RyRs.
Pereira
Laetitia
L
Institut National de la Santé et de la Recherche Médicale U-637, University of Montpellier 1, France.
Matthes
Jan
J
Schuster
Iris
I
Valdivia
Héctor H
HH
Herzig
Stefan
S
Richard
Sylvain
S
Gómez
Ana M
AM
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000502:physiology; D009202:Cardiomyopathies / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium