Vascular endothelin converting enzyme-1 expression and activity is upregulated in clinical diabetes

Mark P. Anstadt, Jimmie Hutchinson, Vera Portik-Dobos, Farahdiba Jafri, Mary Bannan, Kwabena Mawulawde, Adviye Ergul

Research output: Contribution to journalArticle

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Abstract

Circulating and vascular endothelin-1 (ET-1) levels are elevated in diabetes, but the molecular components of the enzymatic activation of ET-1 in the vasculature remains unknown. Furthermore, the distribution of ET receptors favors a contractile phenotype in African Americans with diabetes. Whether there is any difference in local ET-1 activation in this population is unknown. This study examined the expression and activity of ET converting enzyme-1 subisoforms (ECE-1) in the internal mammary artery specimens obtained from patients undergoing coronary artery bypass grafting. The study groups included African-American (AA) and Caucasian (CA), nondiabetic (ND) and diabetic (D) patients: AAND N=10, CAND N=9, AAD N=9, and CAD N=11. The expression of ECE-1a, ECE-1b and ECE-1c subisoforms was studied by RT-PCR. ECE-1a was upregulated 2- and 4-fold in the CAD and AAD groups, respectively (P<.05). In African-American patient groups, ECE-1 activity (fmol/mg protein.h) was augmented from 2,804 ± 185 in nondiabetic tissue samples to 6,857 ± 393 in the diabetic tissue (P<.05). There was a similar increase in the CAD group, which did not significantly differ from AA diabetics. ECE-1 inhibitors, phosphoramidon and FR-901533, inhibited vascular ECE-1 activity by more than 80%. While neutral endopeptidase (NEP) and matrix metalloproteinase-2 (MMP-2) are able to process big ET-1, inhibitors of NEP (thiorphan) and MMP (batimistat) did not affect ECE-1 activity. In conclusion, the enzymatic pathway essential for generating vascular ET-1 is activated in the vasculature of both AA and CA diabetic patients and this activation is highly specific for ECE-1.

Original languageEnglish (US)
JournalEthnicity and Disease
Volume12
Issue number4
StatePublished - Sep 1 2002
Externally publishedYes

Fingerprint

Endothelin-1
Blood Vessels
African Americans
Enzymes
Neprilysin
Thiorphan
Patient Participation
Mammary Arteries
Matrix Metalloproteinase 2
Matrix Metalloproteinases
Coronary Artery Bypass
Endothelin-Converting Enzymes
Phenotype
Polymerase Chain Reaction
Population
Proteins

Keywords

  • African-American
  • Diabetes
  • Endothelin converting enzyme

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Medicine(all)

Cite this

Anstadt, M. P., Hutchinson, J., Portik-Dobos, V., Jafri, F., Bannan, M., Mawulawde, K., & Ergul, A. (2002). Vascular endothelin converting enzyme-1 expression and activity is upregulated in clinical diabetes. Ethnicity and Disease, 12(4).

Vascular endothelin converting enzyme-1 expression and activity is upregulated in clinical diabetes. / Anstadt, Mark P.; Hutchinson, Jimmie; Portik-Dobos, Vera; Jafri, Farahdiba; Bannan, Mary; Mawulawde, Kwabena; Ergul, Adviye.

In: Ethnicity and Disease, Vol. 12, No. 4, 01.09.2002.

Research output: Contribution to journalArticle

Anstadt, MP, Hutchinson, J, Portik-Dobos, V, Jafri, F, Bannan, M, Mawulawde, K & Ergul, A 2002, 'Vascular endothelin converting enzyme-1 expression and activity is upregulated in clinical diabetes', Ethnicity and Disease, vol. 12, no. 4.
Anstadt MP, Hutchinson J, Portik-Dobos V, Jafri F, Bannan M, Mawulawde K et al. Vascular endothelin converting enzyme-1 expression and activity is upregulated in clinical diabetes. Ethnicity and Disease. 2002 Sep 1;12(4).
Anstadt, Mark P. ; Hutchinson, Jimmie ; Portik-Dobos, Vera ; Jafri, Farahdiba ; Bannan, Mary ; Mawulawde, Kwabena ; Ergul, Adviye. / Vascular endothelin converting enzyme-1 expression and activity is upregulated in clinical diabetes. In: Ethnicity and Disease. 2002 ; Vol. 12, No. 4.
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abstract = "Circulating and vascular endothelin-1 (ET-1) levels are elevated in diabetes, but the molecular components of the enzymatic activation of ET-1 in the vasculature remains unknown. Furthermore, the distribution of ET receptors favors a contractile phenotype in African Americans with diabetes. Whether there is any difference in local ET-1 activation in this population is unknown. This study examined the expression and activity of ET converting enzyme-1 subisoforms (ECE-1) in the internal mammary artery specimens obtained from patients undergoing coronary artery bypass grafting. The study groups included African-American (AA) and Caucasian (CA), nondiabetic (ND) and diabetic (D) patients: AAND N=10, CAND N=9, AAD N=9, and CAD N=11. The expression of ECE-1a, ECE-1b and ECE-1c subisoforms was studied by RT-PCR. ECE-1a was upregulated 2- and 4-fold in the CAD and AAD groups, respectively (P<.05). In African-American patient groups, ECE-1 activity (fmol/mg protein.h) was augmented from 2,804 ± 185 in nondiabetic tissue samples to 6,857 ± 393 in the diabetic tissue (P<.05). There was a similar increase in the CAD group, which did not significantly differ from AA diabetics. ECE-1 inhibitors, phosphoramidon and FR-901533, inhibited vascular ECE-1 activity by more than 80{\%}. While neutral endopeptidase (NEP) and matrix metalloproteinase-2 (MMP-2) are able to process big ET-1, inhibitors of NEP (thiorphan) and MMP (batimistat) did not affect ECE-1 activity. In conclusion, the enzymatic pathway essential for generating vascular ET-1 is activated in the vasculature of both AA and CA diabetic patients and this activation is highly specific for ECE-1.",
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AB - Circulating and vascular endothelin-1 (ET-1) levels are elevated in diabetes, but the molecular components of the enzymatic activation of ET-1 in the vasculature remains unknown. Furthermore, the distribution of ET receptors favors a contractile phenotype in African Americans with diabetes. Whether there is any difference in local ET-1 activation in this population is unknown. This study examined the expression and activity of ET converting enzyme-1 subisoforms (ECE-1) in the internal mammary artery specimens obtained from patients undergoing coronary artery bypass grafting. The study groups included African-American (AA) and Caucasian (CA), nondiabetic (ND) and diabetic (D) patients: AAND N=10, CAND N=9, AAD N=9, and CAD N=11. The expression of ECE-1a, ECE-1b and ECE-1c subisoforms was studied by RT-PCR. ECE-1a was upregulated 2- and 4-fold in the CAD and AAD groups, respectively (P<.05). In African-American patient groups, ECE-1 activity (fmol/mg protein.h) was augmented from 2,804 ± 185 in nondiabetic tissue samples to 6,857 ± 393 in the diabetic tissue (P<.05). There was a similar increase in the CAD group, which did not significantly differ from AA diabetics. ECE-1 inhibitors, phosphoramidon and FR-901533, inhibited vascular ECE-1 activity by more than 80%. While neutral endopeptidase (NEP) and matrix metalloproteinase-2 (MMP-2) are able to process big ET-1, inhibitors of NEP (thiorphan) and MMP (batimistat) did not affect ECE-1 activity. In conclusion, the enzymatic pathway essential for generating vascular ET-1 is activated in the vasculature of both AA and CA diabetic patients and this activation is highly specific for ECE-1.

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