Communication between myocytes and fibroblasts in cardiac remodeling in angiotensin chimeric mice
Taiji Matsusaka, … , Agnes Fogo, Iekuni Ichikawa
Taiji Matsusaka, … , Agnes Fogo, Iekuni Ichikawa
Published May 15, 1999
Citation Information: J Clin Invest. 1999;103(10):1451-1458. https://doi.org/10.1172/JCI5056.
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Article

Communication between myocytes and fibroblasts in cardiac remodeling in angiotensin chimeric mice

Abstract

To characterize the mode of action of angiotensin II (Ang II) in cardiac remodeling, we generated chimeric mice that are made of both homozygous Ang II receptor type 1A gene (Agtr1a) null mutant cells and Agtr1a intact cells expressing the lacZ gene (ROSA26). Both Agtr1a null and intact myocytes and interstitial cells independently form areas that are randomly distributed throughout the heart. The distribution of ROSA26 cardiomyocytes overlaps completely with that of Ang II binding, indicating that the majority of Ang II receptors reside on cardiomyocytes. When Ang II (1 ng/g body weight/min) was infused for 2 weeks, mice developed mild to moderate hypertension. The proliferating cardiac fibroblasts identified by bromodeoxyuridine staining were present predominantly in the areas surrounded by Agtr1a intact cardiomyocytes. When control chimeric mice made of wild-type cells and ROSA26 cells (i.e., both carrying intact Agtr1a) were infused with Ang II, fibroblast proliferation was found equally in these cardiomyocyte types. When compared with Agtr1a null mutant chimeras, the control chimeras had more extensive cardiac fibrosis, most prominently in perivascular regions. Therefore, in response to Ang II, cardiac fibroblasts proliferate through both the local and systemic action of Ang II. Importantly, the former is determined by the Ang II receptor of neighboring cardiomyocytes, indicating that a communication between myocytes and fibroblasts plays an important role during Ang II–dependent cardiac remodeling.

Authors

Taiji Matsusaka, Hideyuki Katori, Tadashi Inagami, Agnes Fogo, Iekuni Ichikawa

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Figure 1

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Schematic presentation of the cells constituting the 2 kinds of chimeric...
Schematic presentation of the cells constituting the 2 kinds of chimeric mice engineered in the present study. In the Agtr1a–/–↔ROSA chimeric mouse (a), which is made of ROSA26 transgenic (ROSA) cells and Agtr1a–/– cells, only lacZ-positive cells (derived from a ROSA26 transgenic mouse) express AT1A receptors, whereas lacZ-negative cells lack AT1A receptors because of null mutation of both of their Agtr1a alleles by gene targeting. A comparison between the lacZ-positive and lacZ-negative cells within a given tissue allows identification of the AT1A receptor–dependent local cellular effect of Ang II. In the Agtr1a+/+↔ROSA chimeric mouse (b), which is made of ROSA cells and wild-type cells, both lacZ-positive and lacZ-negative cells express AT1A receptors. Comparison between the lacZ-positive and lacZ-negative cells in this control chimera allows detection of the effect of the ROSA26 mutation and the genetic background of ROSA and non-ROSA cells, which may be significant independently of AT1A receptors because both cells have the intact Agtr1a gene.