Manipulation of beta-adrenergic receptor in pressure-overloaded murine hearts mimics adverse and reverse cardiac remodeling

Abstract

Transverse aortic constriction (TAC) has been widely used to create pressure overload induced heart failure in mice. However, this conventional model has some limitations such as low reproducibility and long creation period of cardiac failure.In order to establish a highly reproducible cardiac failure model that mimics adverse cardiac remodeling (ACR) we combined pressure overload and beta-adrenergic receptor stimuli using isoproterenol (ISO) and explored the optimal TAC model by changing the durations of TAC and the doses of ISO. Thus we constructed a suitable model for ACR with an effective combination of 3-week TAC and subsequent one-week ISO (3 mg/kg/day) infusion. Using RNA-Seq analyses, we identified that the up-regulated genes were mainly related to fibrosis including Fbn1, C1qtnf6 and Loxl2; and that the down-regulated genes were associated with mitochondrial function including Uqcrc1, Ndufs3, and Idh2 in failing hearts of our ACR model. Next, we followed the changes in cardiac function after ceasing ISO infusion. Left ventricular function gradually recovered after cessation of ISO, suggesting cardiac reverse remodeling (CRR). Gene expression signatures of hearts, which exhibited CRR, were almost identical to that of TAC hearts without ISO. In conclusion, our new model exhibits a transition to ACR and subsequent CRR with high reproducibility. This murine model might add new insights into the experiments of heart failure technically as well as scientifically.