Berberine improves cardiac insufficiency through AMPK/PGC-1α signaling-mediated mitochondrial homeostasis and apoptosis in HFpEF mice

Abstract

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for approximately half of cases of HF and is frequently clinically underdiagnosed. Although new therapies continue to emerge, determining optimal treatment strategies persists as a key clinical dilemma. Berberine(BBR), an isoquinoline alkaloid, is known to attenuate HF with reduced ejection fraction.

Purpose: In this study, we explored the cardiovascular benefits of BBR in diastolic dysfunction associated with HFpEF, both in vitro and in vivo.

Methods: In vivo, adult male mice were fed with chow or a high-fat diet (60 % calories from lard) with L-NAME (0.5 g/L in drinking water) for 15 weeks. During the last 4 weeks, BBR (100 mg/Kg/d and 200 mg/Kg/d) was administered orally. Rat cardiac myoblast H9C2 cells were pretreated with BBR for 2 h, followed by exposure to palmitic acid (PA, 100 μM) for 24 h.

Results: Exposure to a high-fat stimulation led to p-AMPK and PGC-1α downregulation, apoptotic cascade activation, elevated mt-ROS production, and disruption of mitochondrial homeostasis both in vivo and in vitro. Notably, BBR intervention elevated the expressions of p-AMPK and PGC-1α, inhibited apoptotic reaction, reduced mt-ROS, ameliorated TFAM/NRF1-mediated mitochondrial biogenesis disorder, alleviated mitochondrial impairment, and improved cardiac function. On the other hand, AMPK knockdown abolished the beneficial impact of BBR. Collectively, our findings underscored the cardioprotective role of BBR in maintaining mitochondrial homeostasis and preventing apoptosis, achieved through the modulation of the AMPK/PGC-1α pathway.

Conclusions: In summary, BBR possesses protective activity against cardiac insufficiency in HFpEF by maintaining mitochondrial homeostasis and inhibiting apoptosis.

Keywords: Berberine; Heart failure with preserved ejection fraction; Mitochondrial homeostasis; Palmitic acid.