Hyperglycemia Inhibits Capacitative Calcium Entry and Hypertrophy in Neonatal Cardiomyocytes

  1. Yi Pang,
  2. Dacia L. Hunton,
  3. Pam Bounelis and
  4. Richard B. Marchase
  1. From the Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama

    Abstract

    Hyperglycemia alters cardiac function and often leads to diabetic cardiomyopathy as cardiomyocyte apoptosis causes a hypertrophied heart to deteriorate to dilation and failure. Paradoxically, many short-term animal models of hyperglycemia protect against ischemia-induced damage, including apoptosis, by limiting Ca2+ overload. We have determined that, like nonexcitable cells, both neonatal and adult cardiomyocytes respond to depletion of sarcoplasmic/endoplasmic reticulum Ca2+ stores with an influx of extracellular Ca2+ through channels distinct from voltage-gated Ca2+ channels, a process termed capacitative Ca2+ entry (CCE). Here, we demonstrate that in neonatal rat cardiomyocytes, hyperglycemia decreased CCE induced by angiotensin II or the Ca2+ATPase inhibitor thapsigargin. Hyperglycemia also significantly blunted Ca2+-dependent hypertrophic responses by ∼60%, as well as the Ca2+-sensitive nuclear translocation of a chimeric protein bearing the nuclear localization signal of a nuclear factor of activated T-cells transcription factor. The attenuation of CCE by hyperglycemia was prevented by azaserine, an inhibitor of hexosamine biosynthesis, and partially by inhibitors of oxidative stress. This complements previous work showing that increasing hexosamine metabolites in neonatal cardiomyocytes also inhibited CCE. The inhibition of CCE by hyperglycemia thus provides a likely explanation for the transition to diabetic cardiomyopathy as well as to the protection afforded to injury after ischemia/reperfusion in diabetic models.

    Footnotes

    • Address correspondence and reprint requests to Richard B. Marchase, University of Alabama at Birmingham, Department of Cell Biology, 1530 3rd Avenue South, MCLM 690, Birmingham, AL 35294-0005. E-mail: marchase{at}uab.edu.

      Received for publication 7 June 2002 and accepted in revised form 23 August 2002.

      ANF, atrial natriuretic factor; Ang II, angiotensin II; AOAC, aminooxyacetic acid; [Ca2+]i, cytoplasmic free Ca2+ concentration; CaM, calmodulin; CCE, capacitative Ca2+ entry; DMEM, Dulbecco’s modified Eagle’s medium; EGFP, enhanced green fluorescent protein; ER, endoplasmic reticulum; HBSS, Hanks’ balanced salt solution; IP3, inositol (1,4,5) triphosphate; NFAT, nuclear factor of activated T-cells; NRVM, neonatal rat ventricular myocyte; MAP, mitogen-activated protein; PE, phenylephrine; PKC, protein kinase C; PLC, phospholipase C; SERCA, SR/ER Ca2+ ATPase; SR, sarcoplasmic reticulum; TTFA, thenoyltrifluoroacetone.

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