Overexpression of the human angiotensin II type 1 receptor in the rat heart augments load induced cardiac hypertrophy

Abstract.

Angiotensin II is known to stimulate cardiac hypertrophy and contractility. Most angiotensin II effects are mediated via membrane bound AT₁ receptors. However, the role of myocardial AT₁ receptors in cardiac hypertrophy and contractility is still rarely defined. To address the hypothesis that increased myocardial AT₁ receptor density causes cardiac hypertrophy apart from high blood pressure we developed a transgenic rat model which expresses the human AT₁ receptor under the control of the α-myosin heavy-chain promoter specifically in the myocardium. Expression was identified and quantified by northern blot analysis and radioligand binding assays, demonstrating overexpression of angiotensin II receptors in the transgenic rats up to 46 times the amount seen in nontransgenic rats. Coupling of the human AT₁ receptor to rat G proteins and signal transduction cascade was verified by sensitivity to GTP-γ-S and increased sensitivity of intracellular Ca²⁺ [Ca²⁺]_i to angiotensin II in fluo-3 loaded transgenic cardiomyocytes. Transgenic rats exhibited normal cardiac growth and function under baseline conditions. Pronounced hypertrophic growth and contractile responses to angiotensin II, however, were noted in transgenic rats challenged by volume and pressure overload. In summary, we generated a new transgenic rat model that exhibits an upregulated myocardial AT₁ receptor density and demonstrates augmented cardiac hypertrophy and contractile response to angiotensin II after volume and pressure overload, but not under baseline conditions.