Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 288, Issue 5, Pages H2521-H2526Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00991.2004
Keywords
thyroid hormone; myocardial hypertrophy
Funding
- NHLBI NIH HHS [K02 HL-04495, R01 HL-056633, HL-07413-22, T32 HL007413] Funding Source: Medline
- NICHD NIH HHS [2K12 HD-27748-12] Funding Source: Medline
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In the heart, elevated thyroid hormone leads to upregulation of metabolic pathways associated with energy production and development of hypertrophy. The malate/ aspartate shuttle, which transfers cytosolicreducing equivalents into the cardiac mitochondria, is increased 33% in hyperthyroid rats. Within the shuttle, the aspartate- glutamate carrier is rate limiting. The excitatory amino acid transporter type 1 ( EAAT1) functions as a glutamate carrier in the malate/ aspartate shuttle. In this study, we hypothesize that EAAT1 is regulated by thyroid hormone. Adult rats were injected with triiodothyronine ( T-3) or saline over a period of 8 - 9 days or provided with propylthiouracil ( PTU) in their drinking water for 2 mo. Steady- state mRNA levels of EAAT1 and aralar1 and citrin ( both cardiac mitochondrial aspartate- glutamate transporters) were determined by Northern blot analysis and normalized to 18S rRNA. A spectrophotometric assay of maximal malate/ aspartate shuttle activity was performed on isolated cardiac mitochondria from PTU- treated and control animals. Protein lysates from mitochondria were separated by SDS- PAGE and probed with a human anti- EAAT1 IgG. Compared with control, EAAT1 mRNA levels ( arbitrary units) were increased nearly threefold in T-3- treated ( 3.1 +/- 0.5 vs. 1.1 +/- 0.2; P < 0.05) and decreased in PTU- treated ( 2.0 +/- 0. 3 vs. 5.2 +/- 1; P < 0.05) rats. Aralar1 mRNA levels were unchanged in T3- treated and somewhat decreased in PTU- treated ( 7.1 +/- 1.0 vs. 9.3 +/- 0.1, P < 0.05) rats. Citrin mRNA levels were decreased in T3- treated and unchanged in PTU- treated rats. EAAT1 protein levels ( arbitrary units) in T3- treated cardiac mitochondria were increased compared with controls ( 8.9 +/- 0.4 vs. 5.9 +/- 0.6; P < 0.005) and unchanged in PTU- treated mitochondria. No difference in malate/ aspartate shuttle capacity was found between PTU- treated and control cardiac mitochondria. Hyperthyroidism in rats is related to an increase in cardiac expression of EAAT1 mRNA and protein. The 49% increase in EAAT1 mitochondrial protein level shows that malate/ aspartate shuttle activity increased in hyperthyroid rat cardiac mitochondria. Although hypothyroidism resulted in a decrease in EAAT1 mRNA, neither the EAAT1 protein level nor shuttle activity was affected. EAAT1 regulation by thyroid hormone may facilitate increased metabolic demands of the cardiomyocyte during hyperthyroidism and impact cardiac function in hyperthyroidism.
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