Berberine improves pressure overload-induced cardiac hypertrophy and dysfunction through enhanced autophagy

Li, Minghui; Zhang, Yaojun; Yu, Yi-Hui; Yang, Shaohua; Iqbal, Javaid; Mi, Qiong‐Yu; Li, Bing; Wang, Zhimei; Mao, Wenxing; Xie, Hong‐Guang

doi:10.1016/j.ejphar.2014.01.061

Cited by 105 publications

(76 citation statements)

References 49 publications

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“…In this study, we observed that AMPK inhibition by compound C effectively reduced the CaSR-augmented autophagy level in Ang II-induced cardiomyocytes. These results revealed that the inhibition of CaSR in the CaMKK β -AMPK-mTOR signaling pathway might contribute to its cardiac cytoprotection, in agreement with previous studies [41,42].…”

Section: +supporting

confidence: 93%

Calhex231 Ameliorates Cardiac Hypertrophy by Inhibiting Cellular Autophagy in Vivo and in Vitro

Liu

Wang

Sun

et al. 2015

Cell Physiol Biochem

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Background/Aims: Intracellular calcium concentration ([Ca²⁺]_i) homeostasis, an initial factor of cardiac hypertrophy, is regulated by the calcium-sensing receptor (CaSR) and is associated with the formation of autolysosomes. The aim of this study was to investigate the role of Calhex₂₃₁, a CaSR inhibitor, on the hypertrophic response via autophagy modulation. Methods: Cardiac hypertrophy was induced by transverse aortic constriction (TAC) in 40 male Wistar rats, while 10 rats underwent a sham operation and served as controls. Cardiac function was monitored by transthoracic echocardiography, and the hypertrophy index was calculated. Cardiac tissue was stained with hematoxylin and eosin (H&E) or Masson's trichrome reagent and examined by transmission electron microscopy. An angiotensin II (Ang II)-induced cardiomyocyte hypertrophy model was established and used to test the involvement of active molecules. Intracellular calcium concentration ([Ca²⁺]_i) was determined by the introduction of Fluo-4/AM dye followed by confocal microscopy. The expression of various active proteins was analyzed by western blot. Results: The rats with TAC-induced hypertrophy had an increased heart size, ratio of heart weight to body weight, myocardial fibrosis, and CaSR and autophagy levels, which were suppressed by Calhex₂₃₁. Experimental results using Ang II-induced hypertrophic cardiomyocytes confirmed that Calhex₂₃₁ suppressed CaSR expression and downregulated autophagy by inhibiting the Ca²⁺/calmodulin-dependent-protein kinase-kinase-β (CaMKK_β)- AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway to ameliorate cardiomyocyte hypertrophy. Conclusions: Calhex₂₃₁ ameliorates myocardial hypertrophy induced by pressure-overload or Ang II via inhibiting CaSR expression and autophagy. Our results may support the notion that Calhex₂₃₁ can become a new therapeutic agent for the treatment of cardiac hypertrophy.

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Section: +supporting

confidence: 93%

Calhex231 Ameliorates Cardiac Hypertrophy by Inhibiting Cellular Autophagy in Vivo and in Vitro

Liu

Wang

Sun

et al. 2015

Cell Physiol Biochem

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“…Earlier studies have demonstrated that BBR could block apoptosis in prevention of endothelial dysfunction associated with diabetes and cardiovascular disease in part through AMPK activation [43,44]. BBR down-regulated p38 MAPK signaling pathway in colonic macrophages and epithelial cells in response to dextran sulfate sodium treatment in vivo [45]; BBR attenuated left ventricular remodeling and cardiomyocyte apoptosis associated with enhanced autophagy through inhibition of p38 MAPK signalling pathway [33]. Nevertheless, the precise mechanisms of AMPK and p38 MAPK regulate the chondroprotective effect of BBR are not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…BBR is an isoquinoline alkaloid, the anti-apoptotic property of which has been applied extensively to a variety of diseases [25,32,33]. Attenuating the process of apoptosis [8,34].…”

Section: Discussionmentioning

confidence: 99%

Berberine prevents nitric oxide-induced rat chondrocyte apoptosis and cartilage degeneration in a rat osteoarthritis model via AMPK and p38 MAPK signaling

et al. 2015

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Chondrocyte apoptosis is an important mechanism involved in osteoarthritis (OA). Berberine (BBR), a plant alkaloid derived from Chinese medicine, is characterized by multiple pharmacological effects, such as anti-inflammatory and anti-apoptotic activities. This study aimed to evaluate the chondroprotective effect and underlying mechanisms of BBR on sodium nitroprusside (SNP)-stimulated chondrocyte apoptosis and surgically-induced rat OA model. The in vitro results revealed that BBR suppressed SNP-stimulated chondrocyte apoptosis as well as cytoskeletal remodeling, down-regulated expressions of inducible nitric oxide synthase (iNOS) and caspase-3, and up-regulated Bcl-2/Bax ratio and Type II collagen (Col II) at protein levels, which were accompanied by increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and decreased phosphorylation of p38 mitogen-activated protein kinase (MAPK). Furthermore, the anti-apoptotic effect of BBR was blocked by AMPK inhibitor Compound C (CC) and adenosine-9-β-D-arabino-furanoside (Ara A), and enhanced by p38 MAPK inhibitor SB203580. In vivo experiment suggested that BBR ameliorated cartilage degeneration and exhibited an anti-apoptotic effect on articular cartilage in a rat OA model, as demonstrated by histological analyses, TUNEL assay and immunohistochemical analyses of caspase-3, Bcl-2 and Bax expressions. These findings suggest that BBR suppresses SNP-stimulated chondrocyte apoptosis and ameliorates cartilage degeneration via activating AMPK signaling and suppressing p38 MAPK activity.

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“…Recently, we have also demonstrated that Notch1 signaling plays a key role in BBR's cardioprotective action [15] . Interestingly, another recent study by Li et al reported that BBR reduced myocardial ER stress in a rat model of cardiac hypertrophy through an autophagy-dependent mechanism [12] . However, to the best of our knowledge, it is still unknown whether BBR attenuates the ER stress caused by MI/R injury.…”

Section: Acta Pharmacologica Sinicamentioning

confidence: 99%

“…Intriguingly, numerous clinical trials [6][7][8][9][10] . BBR has been found to prevent ischemia-induced ventricular tachyarrhythmias, enhance the force of cardiac contractions, and decrease peripheral vascular resistance and blood pressure [11][12][13][14] . Recently, we have also demonstrated that Notch1 signaling plays a key role in BBR's cardioprotective action [15] .…”

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confidence: 99%

Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress

et al. 2016

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Aim: Berberine (BBR), an isoquinoline-derived alkaloid isolated from Rhizoma coptidis, exerts cardioprotective effects. Because endoplasmic reticulum (ER) stress plays a pivotal role in myocardial ischemia/reperfusion (MI/R)-induced apoptosis, it was interesting to examine whether the protective effects of BBR resulted from modulating ER stress levels during MI/R injury, and to define the signaling mechanisms in this process. Methods: Male rats were treated with BBR (200 mg·kg -1 ·d -1 , ig) for 2 weeks, and then subjected to MI/R surgery. Cardiac dimensions and function were assessed using echocardiography. Myocardial infarct size and apoptosis was examined. Total serum LDH levels and CK activities, superoxide production, MDA levels and the antioxidant SOD activities in heart tissue were determined. An in vitro study was performed on cultured rat embryonic myocardium-derived cells H9C2 exposed to simulated ischemia/reperfusion (SIR). The expression of apoptotic, ER stress-related and signaling proteins were assessed using Western blot analyses. Results: Pretreatment with BBR significantly reduced MI/R-induced myocardial infarct size, improved cardiac function, and suppressed myocardial apoptosis and oxidative damage. Furthermore, pretreatment with BBR suppressed MI/R-induced ER stress, evidenced by down-regulating the phosphorylation levels of myocardial PERK and eIF2α and the expression of ATF4 and CHOP in heart tissues. Pretreatment with BBR also activated the JAK2/STAT3 signaling pathway in heart tissues, and co-treatment with AG490, a specific JAK2/STAT3 inhibitor, blocked not only the protective effects of BBR, but also the inhibition of BBR on MI/R-induced ER stress. In H9C2 cells, treatment with BBR (50 μmol/L) markedly reduced SIR-induced cell apoptosis, oxidative stress and ER stress, which were abolished by transfection with JAK2 siRNA. Conclusion: BBR ameliorates MI/R injury in rats by activating the AK2/STAT3 signaling pathway and attenuating ER stress-induced apoptosis.Keywords: berberine; myocardial ischemia/reperfusion injury; apoptosis; ER stress; oxidative stress; JAK2/STAT3; AG490 Acta Pharmacologica Sinica (2016) 37: 354-367; doi: 10.1038/aps.2015 published online 25 Jan 2016 Original Article # These authors contributed equally to this work. * To whom correspondence should be addressed. E-mail yunwangww@163.com (Yun WANG);shiqiangyu210@126.com (Shi-qiang YU) Received 2015-08-26 Accepted 2015-11-20 IntroductionIschemic heart disease remains the leading cause of mortality and disability worldwide. Although timely reperfusion therapy is the primary treatment, reperfusion itself results in major cardiac damage, commonly referred to as myocardial ischemia/reperfusion (MI/R) injury [1,2] . The endoplasmic reticulum (ER) is a multifunctional organelle in eukaryotic cells, which participates in the biosynthesis and folding of proteins. MI/R injury is known to result in the accumulation of unfolded proteins in the ER, which causes a severe unfolded protein response (UPR). Persistent UPR eventually ...

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Berberine improves pressure overload-induced cardiac hypertrophy and dysfunction through enhanced autophagy

Cited by 105 publications

References 49 publications

Calhex231 Ameliorates Cardiac Hypertrophy by Inhibiting Cellular Autophagy in Vivo and in Vitro

Calhex231 Ameliorates Cardiac Hypertrophy by Inhibiting Cellular Autophagy in Vivo and in Vitro

Berberine prevents nitric oxide-induced rat chondrocyte apoptosis and cartilage degeneration in a rat osteoarthritis model via AMPK and p38 MAPK signaling

Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress

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