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NO and PGI2 in coronary endothelial dysfunction in transgenic mice with dilated cardiomyopathy

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Abstract

Objective

The aim of the present work was to analyze coronary endothelial function in the transgenic mouse model of dilated cardiomyopathy (Tgαq*44 mice).

Methods

Coronary vasodilatation, both NO-dependent (induced by bradykinin) and PGI2-dependent (induced by acetylcholine), was assessed in the isolated hearts of Tgαq*44 and FVB mice. Cardiac function was analyzed in vivo (MRI).

Results

In Tgαq*44 mice at the age of 2–4 months cardiac function was preserved and there were no alterations in endothelial function. By contrast, in Tgαq*44 mice at the age of 14–16 months cardiac function was significantly impaired and NO, but not PGI2-dependent coronary function was altered. Interestingly, the basal level of PGI2 in coronary circulation increased fourfold as compared to FVB mice. Cardiac O2 − production increased 1.5-fold and 3-fold in Tgαq*44 vs. FVB mice at the age of 2–6 and 14–16 months, respectively, and was inhibited by apocynin. Interestingly, inhibition of NADPH oxidase or NOS-3 normalized augmented PGI2 production in Tgαq*44 mice. There was also an increased expression of gp91phox in Tgαq*44 vs. FVB hearts, without evident alterations in the expression of COX-1, COX-2, NOS-3 and PGI2-synthase.

Conclusions

In the mouse model of dilated cardiomyopathy, endothelial dysfunction in coronary circulation is present in the late but not the early stage of heart failure pathology and is characterized by a decrease in NO bioavailability and a compensatory increase in PGI2. Both the decrease in NO activity and the increase in PGI2 activity may result from excessive O2 − production by cardiac NADPH oxidase in Tgαq*44 hearts.

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Acknowledgments

This work was supported by the Polish Ministry of Science and Higher Education (grant no. K/PBW/000077) and by a professorial grant from the Foundation for Polish Science to Stefan Chlopicki. We thank Anna Kowalczyk and Anna Obrusnik for their excellent support with the breeding of the Tgαq*44 animals.

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Authors and Affiliations

  1. Dept. of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, Grzegorzecka 16, Krakow, 31-531, Poland

    Lukasz Drelicharz, Valery Kozlovski, Gabor Csanyi & Stefan Chlopicki (Prof.)

  2. Institute of Nuclear Physics, Polish Academy of Science, Krakow, Poland

    Tomasz Skorka, Sylwia Heinze-Paluchowska & Andrzej Jasinski

  3. Dept. of Pharmacological Analysis, Chair of Pharmacology, Jagiellonian University Medical College, Krakow, Poland

    Anna Gebska, Tomasz Guzik & Rafal Olszanecki

  4. University of Technology, Krakow, Poland

    Leszek Wojnar

  5. Rhode Island Hospital and The Warren Alpert Medical School, Brown University, Providence, RI, USA

    Ulrike Mende

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  1. Lukasz Drelicharz
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  2. Valery Kozlovski
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  3. Tomasz Skorka
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  11. Gabor Csanyi
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Correspondence to Stefan Chlopicki.

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Returned for 1. Revision: 24 September 2007 1. Revision received: 12 November 2007

Returned for 2. Revision: 19 December 2007 2. Revision received: 5 February 2008

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Drelicharz, L., Kozlovski, V., Skorka, T. et al. NO and PGI2 in coronary endothelial dysfunction in transgenic mice with dilated cardiomyopathy. Basic Res Cardiol 103, 417–430 (2008). https://doi.org/10.1007/s00395-008-0723-2

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  • DOI: https://doi.org/10.1007/s00395-008-0723-2

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