Published Online
on July 10, 2006

A more recent version of this article appeared on July 25, 2006

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Submitted on August 5, 2005
Revised on May 16, 2006
Accepted on May 17, 2006

Mice Deficient in Telomerase Activity Develop Hypertension Because of an Excess of Endothelin Production

Gema Pérez-Rivero MS, María P. Ruiz-Torres PhD, Juan V. Rivas-Elena MS, Mirjana Jerkic PhD, María L. Díez-Marques PhD, José M. Lopez-Novoa PhD, María A. Blasco PhD, and Diego Rodríguez-Puyol MD^*

From the Research Unit (G.P.-R., M.P.R.-T., D.R.-P.) and Nephrology Section (D.R.-P.), Principe de Asturias Hospital, Alcalá de Henares, Madrid; Departments of Physiology (M.L.D.-M.) and Medicine (D.R.-P.), Universidad de Alcalá, Alcalá de Henares, Madrid; Physiology Department, Universidad de Salamanca, Salamanca (J.V.R.-E., M.J., J.M.L.-N.); and Centro Nacional de Investigaciones Oncológicas (M.A.B.), Madrid. Spain.

^* To whom correspondence should be addressed. E-mail: drodriguez.hupa{at}salud.madrid.org.

Background--Telomere shortening has been related to vascular dysfunction and hypertension. In the present study, we analyzed the influence of telomerase deficiency and telomere shortening on arterial pressure (AP).

Methods and Results--AP was evaluated in 6-month-old mice lacking the RNA component of the telomerase (terc^-/-) at the first generation and third generation (G3). First generation and G3 mice showed higher AP than wild-type (WT) mice. To analyze the mechanisms involved, mean AP and vascular resistance in response to vasoactive substances were measured in G3 and WT mice. These mice showed similar responses to acetylcholine, N^G-nitro-L-arginine methyl ester, angiotensin II, and losartan administration. Mean AP did not increase after endothelin-1 (ET-1) administration in G3 mice, but it did in WT animals. Bosentan treatment decreased mean AP only in G3 mice. Serum and urine concentrations of ET-1 were higher in terc^-/- than in WT mice. Endothelin-converting enzyme (ECE-1) mRNA expression was higher in terc^-/- animals than in the WT group. FR901533, an ECE antagonist, decreased blood pressure in conscious G3 mice. Studies in mouse embryonic fibroblasts from G3 mice suggest that ECE-1 overexpression could be mediated by reactive oxygen species in an AP-1-dependent mechanism, in which some kinases such as PI3-kinase, Akt, erk1/2, and Jun Kinase could be involved. An increased activity of nicotinamide adenine dinucleotide phosphate oxidase seems to be the main source of reactive oxygen species.

Conclusions--Mice lacking telomerase activity show hypertension as a result of an increase in plasma ET-1 levels, which is a consequence of ECE-1 overexpression. A direct link between telomerase activity and hypertension is reported.

Key words: aging • telomerase • hypertension • endothelin • endothelin-converting enzyme

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