Cardiac phenotype and angiotensin II levels in AT1a, AT 1b, and AT2 receptor single, double, and triple knockouts
AimsOur aim was to determine the contribution of the three angiotensin (Ang) II receptor subtypes (AT1a, AT1b, AT2) to coronary responsiveness, cardiac histopathology, and tissue Ang II levels using mice deficient for one, two, or all three Ang II receptors.Methods and resultsHearts of knockout mice and their wild-type controls were collected for histochemistry or perfused according to Langendorff, and kidneys were removed to measure tissue Ang II. Ang II dose-dependently decreased coronary flow (CF) and left ventricular systolic pressure (LVSP), and these effects were absent in all genotypes deficient for AT1a, independently of AT1band AT2. The deletion of Ang II receptors had an effect neither on the morphology of medium-sized vessels in the heart nor on the development of fibrosis. However, the lack of both AT1subtypes was associated with atrophic changes in the myocardium, a reduced CF and a reduced LVSP. AT1adeletion alone, independently of the presence or absence of AT1band/or AT2, reduced renal Ang II by 50 despite a five-fold rise of plasma Ang II. AT1bdeletion, on top of AT1adeletion (but not alone), further decreased tissue Ang II, while increasing plasma Ang II. In mice deficient for all three Ang II receptors, renal Ang II was located only extracellularly. Conclusion The lack of both AT1subtypes led to a baseline reduction of CF and LVSP, and the effects of Ang II on CF and LVSP were found to be exclusively mediated via AT1a. The lack of AT1aor AT1bdoes not influence the development or maintenance of normal cardiac morphology, whereas deficiency for both receptors led to atrophic changes in the heart. Renal Ang II levels largely depend on AT1binding of extracellularly generated Ang II, and in the absence of all three Ang II receptors, renal Ang II is only located extracellularly.
|Keywords||Angiotensin II, G protein-coupled receptors, Genetically modified animals|
|Persistent URL||dx.doi.org/10.1093/cvr/cvq004, hdl.handle.net/1765/27524|
|Note||Free full text at PubMed|
Esch, van, J.H.M, Gembardt, F, Sterner-Kock, A, Heringer-Walther, S, Le, T.H, Laßner, D, … Walther, T. (2010). Cardiac phenotype and angiotensin II levels in AT1a, AT 1b, and AT2 receptor single, double, and triple knockouts. Cardiovascular Research, 86(3), 401–409. doi:10.1093/cvr/cvq004