Low-dose telmisartan protects against myocardial ischemia/reperfusion injury via dual mechanisms: AMPK activation and AMPK-independent calcium homeostasis.

OBJECTIVE

This study aimed to delineate the cardioprotective mechanisms of low-dose Telmisartan against myocardial ischemia/reperfusion (I/R) injury, specifically by distinguishing between AMPK-dependent and AMPK-independent pathways using AMPK kinase-dead (KD) mouse models.

METHODS

We subjected wild-type (WT) and AMPK KD mice to in vitro cardiomyocyte hypoxia/reoxygenation (H/R) and in vivo I/R models. The effects of Telmisartan (0.1-1 μM in vitro; 0.33 mg/kg in vivo) were assessed on contractile function, calcium transients, mitochondrial superoxide production, apoptosis (TUNEL), infarct size (TTC/Evans Blue), and key protein expression (Western blot).

RESULTS

In WT mice, Telmisartan significantly improved contractile recovery, calcium handling, and reduced infarct size, oxidative stress, and apoptosis. These protective effects were largely AMPK-dependent, as they were abolished in AMPK KD mice. In contrast, the improvements in calcium handling and LKB1 phosphorylation were preserved in KD mice, indicating an AMPK-independent mechanism. Consistently, Telmisartan activated AMPK, phosphorylated cTnI(Ser150), PGC-1α, and increased the Bcl-2/Bax ratio in WT but not KD mice, whereas LKB1 activation occurred independently of AMPK.

CONCLUSION

Low-dose Telmisartan confers cardioprotection against I/R injury via dual mechanisms: it primarily utilizes AMPK-dependent signaling to combat oxidative stress, apoptosis, and infarction, while independently of AMPK, it preserves calcium homeostasis and activates LKB1.