Ivabradine protects rats against myocardial infarction through reinforcing autophagy via inhibiting PI3K/AKT/mTOR/p70S6K pathway

ABSTRACT

Ivabradine (Iva), a heart rate reducing agent that specifically inhibits the pacemaker I(f) ionic current, has been demonstrated to be cardioprotective in many cardiovascular diseases. Autophagy is an evolutionarily conserved metabolic process that regulates cardiac homeostasis. This study is aimed to explore whether autophagy is functionally involved in the cardioprotective effect of Iva in a rat model of myocardial infarction (MI). We observed that Iva treatment (po, 10 mg/kg/day) showed significant recovery on the hemodynamics parameters in MI rats, including left ventricular systolic pressure, left ventricular end diastolic pressure, and maximal ascending/descending rate of left ventricular pressure. Also, Iva treatment dramatically decreased infarct size, inhibited myocardial apoptosis, and reduced the levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in MI rats. Moreover, Iva treatment enhanced autophagy and inhibited PI3K/AKT/mTOR/p70S6K pathway in MI rats. Simultaneously, we observed that autophagy enhancer rapamycin (ip, 10 mg/kg/day) showed similar cardioprotective effects with Iva. Furthermore, we observed that addition of autophagy inhibitor 3-methyladenine (ip, 10 mg/kg/day) counteracted the therapeutic effect of Iva, addressing that Iva attenuated post-MI cardiac injury by enhancing autophagy. In summary, these findings demonstrated that Iva attenuated MI in rats by enhancing autophagy, and PI3K/AKT/mTOR/p70S6K pathway might be involved in the process. Autophagy activation by Iva may be a potential therapeutic strategy for the treatment of MI.

Graphical Abstract

KEYWORDS:

• Ivabradine
• myocardial infarction
• autophagy
• PI3K/AKT/MTOR/p70S6K

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authorship contributions

Yingnan Dai, Conceptualization, Investigation, Data curation, Writing-original draft, Funding acquisition; Yeping Chen: Resources, Supervision; Guoqian Wei: Formal analysis, Visualization, Validation; Li Zha: Methodology, Supervision; Xueqi Li: Conceptualization, Supervision, Methodology, Writing-review&editing.

Highlights

1. Ivabradine (Iva) has a cardioprotective role against myocardial infarction (MI).

2. Autophagy enhancement has a cardioprotective role against MI.

3. Iva enhanced the injured autophagy during MI in rats.

4. Autophagy inhibition abolished the cardioprotective role of Iva against MI.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This research was supported by the Special Fund for Innovation Talents Research of Harbin Science and Technology Bureau under Grant No. 2017RAQXJ172 .