RETRACTED: Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy.

TLDR

The study develops a murine model of pressure‑induced hypertrophy to investigate mechanisms of ANF gene activation and to test whether atrial‑specific inducible expression can be segregated from ventricular expression. The authors induced a 35–45 mmHg pressure gradient via thoracic aortic banding in mice and used a transgenic line with a human ANF promoter driving atrial‑specific T‑antigen expression to monitor immediate‑early gene activation and ANF up‑regulation. The model shows that pressure overload induces immediate‑early genes and a 20‑fold rise in ventricular ANF mRNA without T‑antigen expression, confirming that atrial‑specific inducible ANF expression can be segregated and providing a platform for dissecting ventricular ANF regulation.

Abstract

To study the mechanisms that activate expression of the atrial natriuretic factor (ANF) gene during pressure-induced hypertrophy, we have developed and characterized an in vivo murine model of myocardial cell hypertrophy. We employed microsurgical techniques to produce a stable 35- to 45-mmHg pressure gradient across the thoracic aorta of the mouse that is associated with rapid and transient expression of an immediate-early gene program (c-fos/c-jun/junB/Egr-1/nur-77), an increase in heart weight/body weight ratio, and up-regulation of the endogenous ANF gene. These responses that are identical to those in cultured cell and other in vivo models of hypertrophy. To determine whether tissue-specific and inducible expression of the ANF gene can be segregated, we used a transgenic mouse line in which 500 base pairs of the human ANF promoter region directs atrial-specific expression of the simian virus 40 large tumor antigen (T antigen), with no detectable expression in the ventricles. Thoracic aortic banding of these mice led to a 20-fold increase in the endogenous ANF mRNA in the ventricle but no detectable expression of the T-antigen marker gene. This result provides evidence that atrial-specific and inducible expression of the ANF gene can be segregated, suggesting that a distinct set of regulatory cis sequences may mediate the up-regulation of the ANF gene during in vivo pressure overload hypertrophy. This murine model demonstrates the utility of microsurgical techniques to study in vivo cardiac physiology in transgenic mice and should allow the application of genetic approaches to identify the mechanisms that activate ventricular expression of the ANF gene during in vivo hypertrophy.