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Pathophysiology of Cardiac AT1 and AT2 Receptors

  • Chapter
Angiotensin Vol. II

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 163 / 2))

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Abstract

Cardiac angiotensin II type-1 (ATI ) and angiotensin II type-2 (AT2) play a crucial role in mediating the myocardial effects of angiotensin II (Ang II). AT1 mediates most of the known Ang II effects, whereas the role of AT2 is still controversial. AT2 is the predominant subtype in the human heart and its activation is proposed to counteract AT1-mediated effects. Expression and regulation of AT1 and AT2 is disease dependent and locally inhomogeneous. ATR regulation occurs at different level s and involves rapid desensitization, receptor in ternalization, attenuation of transcription and post-transcriptional mRNA destabilization. Also, alternative splicing of AT1 and AT2 mRNA may represent a mechanism of ATR regulation. AT1 splice patterns differ between controls and failing hearts, possibly leading to differences in AT1 mRNA translation. AT1 content is reduced in LVH, heart failure and in transplanted human hearts. However, data on AT2 regulation are conflicting. Signal transduction following AT1 stimulation is mediated by activation of PKC, the MAP kinase pathway and immediate early genes. In addition, the JAK-STAT pathway, tyrosine phosphorylation and NF-кB seem to be involved. In contrast, AT2 receptor stimulates protein tyrosine phosphatase activity and leads to inhibition of phosphotyrosine phosphatase 1B in fibroblasts. Regulation of the AT2 receptor in human heart occurs also by elements in intron 1. Factors such as nitric oxide, hypercholesterolemia, statins and estrogens are closely related to the expression of the cardiac ATR. Nitric oxide, statins and estrogen can attenuate Ang II-mediated adverse effects and may in part have protective effects in cardiovascular disease. Cardiac RAS and collagen synthesis are activated in human aortic valve stenosis and regurgitation. However, Ang II seems not to be a necessary factor for LVHin most animal models. Genetic data also suggest that AT2 has a role in human LVH. The +1675 G/A-polymorphism of the X-chromosomal located AT2 receptor modulates LV structure in white, young male subjects with normal or mildly elevated blood pressure and is associated with LVH in these subjects. Further understanding of the disease-specific regulation and function of AT1 and AT2 may lead to a differential pharmacotherapy in LVH and early stages of heart failure

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  1. Klinik für Innere Medizin—Kardiologie, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    J. Fielitz & V. Regitz-Zagrosek

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  2. V. Regitz-Zagrosek
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Fielitz, J., Regitz-Zagrosek, V. (2004). Pathophysiology of Cardiac AT1 and AT2 Receptors. In: Angiotensin Vol. II. Handbook of Experimental Pharmacology, vol 163 / 2. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-18497-0_11

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