Liquiritin Attenuates Pathological Cardiac Hypertrophy by Activating the PKA/LKB1/AMPK Pathway

Abstract

Background: Liquiritin (LQ) is one of the main flavonoids extracted from the roots of Glycyrrhiza spp., which are widely used in traditional Chinese medicine. Studies in both cellular and animal disease models have shown that LQ attenuates or prevents oxidative stress, inflammation, and apoptosis. However, the potential therapeutic effects of LQ on pressure overload-induced cardiac hypertrophy have not been so far explored. Therefore, we investigated the cardioprotective role of LQ and its underlying mechanisms in the aortic banding (AB)-induced cardiac hypertrophy mouse model.Methods and Results: Starting 3 days after AB surgery, LQ (80 mg/kg/day) was administered daily over 4 weeks. Echocardiography and pressure-volume loop analysis indicated that LQ treatment markedly improved hypertrophy-related cardiac dysfunction. Moreover, hematoxylin and eosin, picrosirius red, and TUNEL staining showed that LQ significantly inhibited cardiomyocyte hypertrophy, interstitial fibrosis, and apoptosis. Western blot assays further showed that LQ activated LKB1/AMPKα2/ACC signaling and inhibited mTORC1 phosphorylation in cardiomyocytes. Notably, LQ treatment failed to prevent cardiac dysfunction, hypertrophy, and fibrosis in AMPKα2 knockout (AMPKα2−/−) mice. However, LQ still induced LKB1 phosphorylation in AMPKα2−/− mouse hearts. In vitro experiments further demonstrated that LQ inhibited Ang II-induced hypertrophy in neonatal rat cardiomyocytes (NRCMs) by increasing cAMP levels and PKA activity. Supporting the central involvement of the cAMP/PKA/LKB1/AMPKα2 signaling pathway in the cardioprotective effects of LQ, inhibition of Ang II-induced hypertrophy and induction of LKB1 and AMPKα phosphorylation were no longer observed after inhibiting PKA activity.Conclusion: This study revealed that LQ alleviates pressure overload-induced cardiac hypertrophy in vivo and inhibits Ang II-induced cardiomyocyte hypertrophy in vitro via activating cAMP/PKA/LKB1/AMPKα2 signaling. These findings suggest that LQ might be a valuable adjunct to therapeutic approaches for treating pathological cardiac remodeling.

Liquiritin Protects Against Cardiac Fibrosis After Myocardial Infarction by Inhibiting CCL5 Expression and the NF-κB Signaling Pathway

“…20 Recent studies have reported that LQ exerts cardioprotective effects by attenuating oxidative stress injury, reducing the expression of inflammatory factors, inhibiting cell apoptosis, restoring cardiac functional parameters and maintaining structural integrity. [21][22][23] In addition, many traditional Chinese medicine formula containing LQ have been used to treat cardiovascular diseases, especially ischemic heart disease, such as Zhigancao Decoction, 24 Xuefu Zhuyu Decoction, 25 Yangxin Dingji Capsule, 26 etc. However, the effect of LQ on MI-induced damage remains poorly understood.…”

Metrnl ameliorates diabetic cardiomyopathy via inactivation of cGAS/STING signaling dependent on LKB1/AMPK/ULK1-mediated autophagy

“…AMPKα2 is the primary subunit of AMPK in the myocardium and ablation of AMPKα2 leads to pathological cardiac remodeling and dysfunction [21] . Recently, Tang’s group has shown that activation of the cAMP/PKA/LKB1/AMPKα2 signaling pathway underlies the protective effects of Liquiritin against pathological cardiac hypertrophy [22] . Thus, in addition to AMPKα1,we wonder whether Metrnl OE affected AMPKα2 signaling in cardiomyocytes.…”

“…It is likely that the LKB1/AMPK/ULK1/autophagy axis might partially contribute to the beneficial effects of Metrnl on diabetic cardiac injury. The AMPK/mammalian phosphorylation target of rapamycin (mTOR）signaling pathway is an important regulator of DCM [27] , and LKB1 induces AMPKα phosphorylation at Thr 172 within its catalytic subunit, leading to AMPK-mediated inhibition of mTORC1 and subsequent activation of autophagy [22] , [28] , [29] . Thus, we next sought to examine whether mTORC1 was involved in the induction of autophagy mediated by Metrnl.…”

Liquiritin: A natural flavonoid with potential cardiovascular protection

“…Liquiritin could also decrease heart size, cardiac cross-sectional area (CSA), and heart weight/body weight (HW/BW), and inhibited the messenger RNA (mRNA) expression of A type natriuretic peptide (ANP), B type natriuretic peptide (BNP), and β-myosin heavy chain (β-MHC). In vitro, liquiritin inhibited Ang II-induced hypertrophy in neonatal rat cardiomyocytes (NRCMs) via activating cyclic adenosine monophosphate-activated protein/protein kinase/liver kinase B1/AMPKα2 (cAMP/PKA/LKB1/ AMPKα2) signaling (Aiyasiding et al, 2022). Liquiritin could decrease the ATE1 protein levels and TAK1 and JNK1/2 phosphorylation induced by angiotensin II (Ang II), which attenuated Ang II-induced cardiomyocyte hypertrophy by regulating the ATE1/TAK1-JNK1/2 pathway (Mo et al, 2022).…”