Luteolin attenuates sepsis‑induced myocardial�injury by enhancing autophagy in mice

Abstract

Sepsis-induced cardiomyopathy (SIc) is a complication of severe sepsis and septic shock characterized by an invertible myocardial depression. This study sought to explore the potential effects and mechanism of luteolin, a flavonoid polyphenolic compound, in lipopolysaccharide (LPS)-induced myocardial injury. Experimental mice were randomly allocated into 3 groups (25 mice in each group): The control group (Nc), the LPS group (LPS) and the LPS + luteolin group (LPS + Lut). Before the SIc model was induced, luteolin was dissolved in dMSO and injected intraperitoneally for 10 days into LPS + Lut group mice. Nc group and LPS group mice received an equal volume of dMSO for 10 days. On day 11, the animal model of sepsis-induced cardiac dysfunction was induced by intraperitoneal injection of LPS. A total of 12 h after LPS injection, measurements and comparisons were made among the groups. Luteolin administration improved cardiac function, attenuated the inflammatory response, alleviated mitochondrial injury, decreased oxidative stress, inhibited cardiac apoptosis and enhanced autophagy. In addition, luteolin significantly decreased the phosphorylation of AMP-activated protein kinase (AMPK) in septic heart tissue. The protective effect of luteolin was abolished by 3-methyladenine (an autophagy inhibitor) and dorsomorphin (compound c, an AMPK inhibitor), as evidenced by decreased autophagic activity, destabilized mitochondrial membrane potential and increased apoptosis in LPS-treated cardiomyocytes, but was mimicked by 5-aminoimidazole-4-carboxamide ribonucleotide (an AMPK activator), suggesting that luteolin attenuates LPS-induced myocardial injury by increasing autophagy through AMPK activation. Luteolin may be a promising therapeutic agent for treating SIc.

Capsaicin protects cardiomyocytes against lipopolysaccharide-induced damage via 14-3-3γ-mediated autophagy augmentation

“…Besides, after coincubation with BafA1, LC3Ⅱ and P62 levels were significantly improved, indicating that LPS treatment could trigger a low level of autophagy instead of impairment in autophagic flux ( Figure 2A ). Previous studies have suggested that activation of autophagy could contribute to suppressing LPS-induced cell toxicity ( Sun et al, 2018 ; Quach et al, 2019 ; Wu et al, 2020 ), autophagy influences the clearance of damaged proteins and organelles ( Yang and Klionsky, 2010 ). After pretreatment with Cap, LC3Ⅱ was significantly increased and P62 degradation was declined ( Figures 2B–E ).…”

CircTLK1 modulates sepsis‐induced cardiomyocyte apoptosis via enhancing PARP1/HMGB1 axis–mediated mitochondrial DNA damage by sponging miR‐17‐5p

“…Multiple antioxidant enzymes (eg SOD) are crucial to protect against mitochondrial oxidative stress. Mounting evidence has proved that sepsis‐induced myocardial injury could be attenuated by inhibiting oxidative stress and mitochondrial dysfunction 43,44 . A recent research showed that inhibition of PARP1 delayed the progression of Chagasic cardiomyopathy through improving mitochondria function and maintaining oxidant/antioxidant balance 45 .…”

Protective Effects of Flavonoids Against Mitochondriopathies and Associated Pathologies: Focus on the Predictive Approach and Personalized Prevention

“…Impressively, intraperitoneal injection of luteolin in mice with lipopolysaccharide-induced myocardial injury mitigated mitochondrial injury and oxidative stress by decreasing AMPK phosphorylation in septic heart tissue and stabilizing the mitochondrial membrane potential. In summary, luteolin attenuates lipopolysaccharideinduced myocardial injury associated with mitochondrial impairments in mice through the inhibition of apoptosis and enhancing autophagy via modulation of AMPK signaling [16]. Furthermore, icariin, a prenylated flavonol glycoside, protected H9C2 cardiomyocytes from oxidative stress by scavenging ROS and promoting ERK pathway phosphorylation.…”

“…In recent years, the beneficial health effects of flavonoids, naturally occurring polyphenolic compounds, have attracted medical research, including their utilization in pathologies associated with mitochondrial impairments [11] such as cancers, cardiovascular and neurodegenerative diseases [12]. The efficacy of flavonoids is supported by extensive preclinical evidence that represents the basis for further research into the potential future use of these compounds in specific targeted and personalized therapy of mitochondriopathies according to the 3PM approach [13][14][15][16][17][18][19].…”