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Metallothionein abrogates GTP cyclohydrolase I inhibition-induced cardiac contractile and morphological defects: role of mitochondrial biogenesis.

Publication ,  Journal Article
Ceylan-Isik, AF; Guo, KK; Carlson, EC; Privratsky, JR; Liao, S-J; Cai, L; Chen, AF; Ren, J
Published in: Hypertension
June 2009

One key mechanism for endothelial dysfunction is endothelial NO synthase (eNOS) uncoupling, whereby eNOS generates O(2)(*-) rather than NO because of deficient eNOS cofactor tetrahydrobiopterin (BH4). This study was designed to examine the effect of BH4 deficiency on cardiac morphology and function, as well as the impact of metallothionein (MT) on BH4 deficiency-induced abnormalities, if any. Friend virus B (FVB) and cardiac-specific MT transgenic mice were exposed to 2,4-diamino-6-hydroxy-pyrimidine (DAHP; 10 mmol/L, 3 weeks), an inhibitor of the BH4 synthetic enzyme GTP cyclohydrolase I. DAHP reduced plasma BH4 levels by 85% and elevated blood pressure in both FVB and MT mice. Echocardiography found decreased fractional shortening and increased end-systolic diameter in DAHP-treated FVB mice. Cardiomyocytes from DAHP-treated FVB mice displayed enhanced O(2)(*-) production, contractile and intracellular Ca(2+) defects including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, reduced intracellular Ca(2+) rise, and clearance. DAHP triggered mitochondrial swelling/myocardial filament aberrations and mitochondrial O(2)(*-) accumulation, assessed by transmission electron microscopy and MitoSOX Red fluorescence, respectively. DAHP also promoted the N(G)-nitro-l-arginine methyl ester-inhibitable O(2)(*-) production and eNOS phosphorylation at Thr497. Although MT had little effect on cardiac mechanics and ultrastructure, it attenuated DAHP-induced defects in cardiac function, morphology, O(2)(*-) production, and eNOS phosphorylation (Thr497). The DAHP-induced cardiomyocyte mechanical responses were alleviated by in vitro BH4 treatment. DAHP inhibited mitochondrial biogenesis, mitochondrial uncoupling protein 2, and chaperone heat shock protein 90, and all but uncoupling protein 2 were rescued by MT. Our data suggest a role for BH4 deficiency in cardiac dysfunction and the therapeutic potential of antioxidants against eNOS uncoupling in the heart.

Duke Scholars

Published In

Hypertension

DOI

EISSN

1524-4563

Publication Date

June 2009

Volume

53

Issue

6

Start / End Page

1023 / 1031

Location

United States

Related Subject Headings

  • Sugar Acids
  • Sensitivity and Specificity
  • Reverse Transcriptase Polymerase Chain Reaction
  • Random Allocation
  • RNA
  • Probability
  • Oxygen Consumption
  • Nitric Oxide
  • Myocytes, Cardiac
  • Myocardial Contraction
 

Citation

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Ceylan-Isik, A. F., Guo, K. K., Carlson, E. C., Privratsky, J. R., Liao, S.-J., Cai, L., … Ren, J. (2009). Metallothionein abrogates GTP cyclohydrolase I inhibition-induced cardiac contractile and morphological defects: role of mitochondrial biogenesis. Hypertension, 53(6), 1023–1031. https://doi.org/10.1161/HYPERTENSIONAHA.108.123422
Ceylan-Isik, Asli F., Kelly K. Guo, Edward C. Carlson, Jamie R. Privratsky, Song-Jie Liao, Lu Cai, Alex F. Chen, and Jun Ren. “Metallothionein abrogates GTP cyclohydrolase I inhibition-induced cardiac contractile and morphological defects: role of mitochondrial biogenesis.Hypertension 53, no. 6 (June 2009): 1023–31. https://doi.org/10.1161/HYPERTENSIONAHA.108.123422.
Ceylan-Isik AF, Guo KK, Carlson EC, Privratsky JR, Liao S-J, Cai L, et al. Metallothionein abrogates GTP cyclohydrolase I inhibition-induced cardiac contractile and morphological defects: role of mitochondrial biogenesis. Hypertension. 2009 Jun;53(6):1023–31.
Ceylan-Isik, Asli F., et al. “Metallothionein abrogates GTP cyclohydrolase I inhibition-induced cardiac contractile and morphological defects: role of mitochondrial biogenesis.Hypertension, vol. 53, no. 6, June 2009, pp. 1023–31. Pubmed, doi:10.1161/HYPERTENSIONAHA.108.123422.
Ceylan-Isik AF, Guo KK, Carlson EC, Privratsky JR, Liao S-J, Cai L, Chen AF, Ren J. Metallothionein abrogates GTP cyclohydrolase I inhibition-induced cardiac contractile and morphological defects: role of mitochondrial biogenesis. Hypertension. 2009 Jun;53(6):1023–1031.

Published In

Hypertension

DOI

EISSN

1524-4563

Publication Date

June 2009

Volume

53

Issue

6

Start / End Page

1023 / 1031

Location

United States

Related Subject Headings

  • Sugar Acids
  • Sensitivity and Specificity
  • Reverse Transcriptase Polymerase Chain Reaction
  • Random Allocation
  • RNA
  • Probability
  • Oxygen Consumption
  • Nitric Oxide
  • Myocytes, Cardiac
  • Myocardial Contraction