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

To characterize the mode of action of angiotensin II (Ang II) in cardiac re modeling, we generated chimeric mice that are made of both homozygous Ang I I 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 co mpletely with chat of Ang II binding, indicating that the majority of Ang I I receptors reside on cardiomyocytes. When Ang LT (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 Agh la intact cardiom yocytes. When control chimeric mice made of wild-type cells and ROSA26 cell s (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 r esponse to Ang II, cardiac fibroblasts proliferate through both the local a nd systemic action of Ang II. Importantly, the former is determined by the Ang II receptor of neighboring cardiomyocytes, indicating that a communicat ion between myocytes and fibroblasts plays an important role during Ang II- dependent cardiac remodeling.