Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice

Pierre Meneton, May Bloch-Faure, Albert A. Hagege, Hartmut Ruetten, Wei Huang, Sonia Bergaya, Debbie Ceiler, Doris Gehring, Isabelle Martins, Georges Salmon, Chantal M. Boulanger, Jürg Nussberger, Bertrand Crozatier, Jean Marie Gasc, Didier Heudes, Patrick Bruneval, Tom Doetschman, Joël Ménard, François Alhenc-Gelas

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Abstract

Tissue kallikrein is a serine protease thought to be involved in the generation of bioactive peptide kinins in many organs like the kidneys, colon, salivary glands, pancreas, and blood vessels. Low renal synthesis and urinary excretion of tissue kallikrein have been repeatedly linked to hypertension in animals and humans, but the exact role of the protease in cardiovascular function has not been established largely because of the lack of specific inhibitors. This study demonstrates that mice lacking tissue kallikrein are unable to generate significant levels of kinins in most tissues and develop cardiovascular abnormalities early in adulthood despite normal blood pressure. The heart exhibits septum and posterior wall thinning and a tendency to dilatation resulting in reduced left ventricular mass. Cardiac function estimated in vivo and in vitro is decreased both under basal conditions and in response to β-adrenergic stimulation. Furthermore, flow-induced vasodilatation is impaired in isolated perfused carotid arteries, which express, like the heart, low levels of the protease. These data show that tissue kallikrein is the main kinin-generating enzyme in vivo and that a functional kallikrein-kinin system is necessary for normal cardiac and arterial function in the mouse. They suggest that the kallikrein-kinin system could be involved in the development or progression of cardiovascular diseases.

Original languageEnglish (US)
Pages (from-to)2634-2639
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number5
DOIs
StatePublished - Feb 27 2001

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Meneton, P., Bloch-Faure, M., Hagege, A. A., Ruetten, H., Huang, W., Bergaya, S., Ceiler, D., Gehring, D., Martins, I., Salmon, G., Boulanger, C. M., Nussberger, J., Crozatier, B., Gasc, J. M., Heudes, D., Bruneval, P., Doetschman, T., Ménard, J., & Alhenc-Gelas, F. (2001). Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice. Proceedings of the National Academy of Sciences of the United States of America, 98(5), 2634-2639. https://doi.org/10.1073/pnas.051619598