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Mechanical Stress Induces Cardiomyocyte Hypertrophy Through Agonist-Independent Activation of Angiotensin II Type 1 Receptor

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Mechanosensitivity of the Heart

Part of the book series: Mechanosensitivity in Cells and Tissues ((MECT,volume 3))

Abstract

The angiotensin II (AngII) type 1 (AT1) receptor is a seven-transmembrane G protein-coupled receptor that plays a crucial role in the development of load-induced cardiac hypertrophy. Besides systemically and locally generated AngII, mechanical stress can activate the AT1 receptor, and induce cardiac hypertrophy in vivo. In response to stretch stimulation, the AT1 receptor undergoes a specific switch in the receptor conformation without the involvement of AngII. The agonist-independent activation of the AT1 receptor can be inhibited by inverse agonists, but not by neutral antagonists, through the specific drug-receptor interactions. It is conceptually novel that the AT1 receptor, a member of G protein-coupled receptor, is a mechanical force-transducing molecule and mediates mechanical stress-induced cellular responses. In addition, inverse agonist activity emerges as an important pharmacological parameter for the AT1 receptor blockers that determines the efficacy to prevent organ damage in cardiovascular diseases. In this section, molecular and structural bases for mechanosensation by the AT1 receptor and inverse agonism at the AT1 receptor will be discussed.

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Acknowledgements

The authors are supported in part by grants from the Japanese Ministry of Education, Science, Sports, and Culture, from Health and Labor Sciences Research Grants, Japan Health Sciences Foundation (to IK and HA); Takeda Medical Research Foundation, Takeda Science Foundation, Uehara Memorial Foundation, Kato Memorial Trust for Nambyo Research, Japan Medical Association (to IK); from Mochida Memorial Foundation, Japanese Heart Foundation/Novartis Research Award on Molecular and Cellular Cardiology, Japan Intractable Diseases Research Foundation, Kowa Life Science Foundation (to HA).

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  1. Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, 260-8670, Chiba, Japan

    Hiroshi Akazawa

  2. Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan

    Issei Komuro

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  1. Hiroshi Akazawa
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  2. Issei Komuro
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Correspondence to Issei Komuro .

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  1. Dept. Fundamental &, Russian State Medical University, Ostrovitjanova Str. 1, Moskva, 117997, Russian Federation

    Andre Kamkin

  2. Dept. Fundamental &, Russian State Medical University, Ostrovitjanova Str. 1, Moskva, 117997, Russian Federation

    Irina Kiseleva

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Akazawa, H., Komuro, I. (2010). Mechanical Stress Induces Cardiomyocyte Hypertrophy Through Agonist-Independent Activation of Angiotensin II Type 1 Receptor. In: Kamkin, A., Kiseleva, I. (eds) Mechanosensitivity of the Heart. Mechanosensitivity in Cells and Tissues, vol 3. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2850-1_4

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