Two preproendothelin 1 mRNAs transcribed by alternative promoters.

Benatti, Luca; Bonecchi, Loredana; Cozzi, Liviana; Sarmientos, Paolo

doi:10.1172/jci116274

Cited by 25 publications

(13 citation statements)

References 39 publications

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“…Plasmid pBiGN:ET-1 carrying a full-length human ET-1 cDNA 19 ( Figure 1a) was used in pronuclei injections as described previously. 20 Founders identified by polymerase chain reaction (PCR) and Southern blot were backcrossed with C57BL/6, and offspring were bred with ␣MHC-tTA mice.…”

Section: Transgenic Micementioning

confidence: 99%

Conditional Cardiac Overexpression of Endothelin-1 Induces Inflammation and Dilated Cardiomyopathy in Mice

Yang

Gros²,

Kabir³

et al. 2004

Circulation

155

113

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Background-Myocardial expression of endothelin-1 (ET-1) and its receptors ET A and ET B is increased in heart failure.However, the role of ET-1 and its signaling pathways in the pathogenesis of myocardial diseases is unclear. Methods and Results-Human ET-1 cDNA was placed downstream of a promoter responsive to a doxycycline (DOX)-regulated transcriptional activator (tTA). This line (ET ϩ ) was bred with one harboring cardiac myocyterestricted expression of tTA (␣MHC-tTA). Myocardial ET-1 peptide levels were significantly increased in binary transgenic (BT, ET ϩ /tTA ϩ ) compared with nonbinary transgenic (NBT, ET ϩ /tTA Ϫ ; ET Ϫ /tTA ϩ ; ET Ϫ /tTA Ϫ ) or DOX-treated BT littermates (40.1Ϯ4.7 versus 2.6Ϯ1.2 fmol/mL, PϽ0.003). BT mice demonstrated progressive mortality between 5 and 11 weeks after DOX withdrawal, associated with left ventricular dilatation and contractile dysfunction (peak ϩdP/dT, 4673Ϯ468 versus 5585Ϯ658 mm Hg/s, PϽ0.05). An interstitial inflammatory infiltrate, including macrophages and T lymphocytes, was evident in the myocardium of BT mice, associated with sequential increases in nuclear factor-B translocation and expression of tumor necrosis factor-␣, interferon-␥, interleukin-1 and interleukin-6. Significant prolongation of survival was observed with the combined ET A /ET B antagonist LU420627 (nϭ8, PϽ0.05) in BT mice but not the ET A -selective antagonist LU135252 (nϭ5, Pϭ0.9), consistent with an important role for ET B in this model. Conclusions-These are the first data to demonstrate that cardiac overexpression of ET-1 is sufficient to cause increased expression of inflammatory cytokines and an inflammatory cardiomyopathy leading to heart failure and death.

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Section: Transgenic Micementioning

confidence: 99%

Conditional Cardiac Overexpression of Endothelin-1 Induces Inflammation and Dilated Cardiomyopathy in Mice

Yang

Gros²,

Kabir³

et al. 2004

Circulation

155

113

View full text Add to dashboard Cite

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“…The levels of preproET-1 mRNA can be regulated by various chemical and mechanical stimuli such as thrombin, angiotensin II, vasopressin, transforming growth factor-␤, Ca 2+ ionophore, insulin, tumor necrosis factor-␣, hypoxia, and hemodynamical shear stress (17). PKC activation is involved in basal and agonist-induced ET-1 synthesis or secretion in different cell types (18)(19)(20)(21)(22).…”

mentioning

confidence: 99%

Induction of endothelin-1 expression by glucose: an effect of protein kinase C activation.

et al. 2000

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Enhanced actions or levels of endothelin-1 (ET-1), a potent vasoconstrictor, have been associated with decreased blood flow in the retina and peripheral nerves of diabetic animals and may be related to the development of pathologies in these tissues. Hyperglycemia has been postulated to increase ET-1 secretion in endothelial cells. We have characterized the mechanism by which elevation of glucose is increasing ET-1 mRNA expression in capillary bovine retinal endothelial cells (BREC) and bovine retinal pericytes (BRPC). Elevation of glucose, but not mannitol, from 5.5 to 25 mmol/l for 3 days increased membranous protein kinase C (PKC) activities and ET-1 mRNA in parallel levels by 2-fold in BREC and BRPC. These effects were reversed by decreasing glucose levels to 5.5 mmol/l for an additional 2 days. Glucoseinduced ET-1 overexpression was inhibited by a general PKC inhibitor, GF109203X, and a mitogen-activated protein kinase kinase inhibitor, PD98059, but not by wortmannin, a phosphatidylinositol 3-kinase inhibitor. By immunoblot analysis, PKC-␤2 and -␦ isoforms in BREC were significantly increased relative to other isoforms in the membranous fractions when glucose level was increased. Overexpression of PKC-␤1 and -␦ isoforms but not PKC-isoform by adenovirus vectors containing the respective cDNA enhanced in parallel PKC activities, proteins, and basal and glucose-induced ET-1 mRNA expression by at least 2-fold. These results showed that enhanced ET-1 expression induced by hyperglycemia in diabetes is partly due to activation of PKC-␤ and -␦ isoforms, suggesting that inhibition of these PKC isoforms may prevent early changes in diabetic retinopathy and neuropathy.

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“…As a strictly sinusoidal blood collection is technically not feasible, only the quantification of prepro-ETmRNA expression in tissue samples will potentially clarify this question in the future. This molecularbiological technique has only been established in cell culture experiments and has not been transferred to ischemia-reperfusion models so far [16].…”

Section: Discussionmentioning

confidence: 99%

Endothelin-1 and Big-Endothelin Concentrations Are Elevated in Liver Graft Tissue during Cold Storage and Reperfusion

Kraus¹,

Golling²,

Mehrabi³

et al. 2001

Eur Surg Res

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Endothelin (ET) and its precursor big-ET were synchronously analyzed by RIA in liver biopsies and systemic plasma during porcine orthotopic liver transplantation (OLT) before graft harvesting (phase A), after cold storage (phase B), and early (phase C) and late reperfusion (phase D). Tissue and plasma concentrations were correlated with length of survival and reperfusion. Increased tissue ET/big-ET levels were already detected during phase B (ET: 46 ± 20; big-ET: 245 ± 119 pg/mg cytosolic protein) and remained elevated in phase C (ET: 49 ± 16; big-ET: 306 ± 144 pg/mg) compared to baseline (ET: 32 ± 13; big-ET: 185 ± 164 pg/mg; p < 0.05). In phase D, a rapid concentration decline was detected (ET: 36 ± 26; big-ET: 163 ± 138 pg/mg). Systemic ET levels were elevated in phase B (3.4 ± 3.0 pg/ml), C, (2.8 ± 1.2 pg/ml) and D (2.6 ± 2.0 pg/ml), compared to baseline (1.7 ± 1.1 pg/ml; p < 0.05). ET/big-ET kinetics in liver tissue and systemic plasma showed analogous characteristics. Intrahepatic ET accumulation during storage and early reperfusion could be of relevance for harvest-related disturbances of hepatic microcirculation.

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Two preproendothelin 1 mRNAs transcribed by alternative promoters.

Cited by 25 publications

References 39 publications

Conditional Cardiac Overexpression of Endothelin-1 Induces Inflammation and Dilated Cardiomyopathy in Mice

Conditional Cardiac Overexpression of Endothelin-1 Induces Inflammation and Dilated Cardiomyopathy in Mice

Induction of endothelin-1 expression by glucose: an effect of protein kinase C activation.

Endothelin-1 and Big-Endothelin Concentrations Are Elevated in Liver Graft Tissue during Cold Storage and Reperfusion

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