Ginsenoside Rg1 attenuates mechanical stress-induced cardiac injury via calcium sensing receptorrelated pathway

다국어 초록 (Multilingual Abstract)

Background: Ginsenoside Rg1 (Rg1) has been well documented to be effective against various cardiovasculardisease. The aim of this study is to evaluate the effect of Rg1 on mechanical stress-inducedcardiac injury and its possible mechanism with a focus on the calcium sensing receptor (CaSR)signaling pathway.
Methods: Mechanical stress was implemented on rats through abdominal aortic constriction (AAC)procedure and on cardiomyocytes and cardiac fibroblasts by mechanical stretching with Bioflex CollagenI plates. The effects of Rg1 on cell hypertrophy, fibrosis, cardiac function, [Ca2þ]i, and the expression ofCaSR and calcineurin (CaN) were assayed both on rat and cellular level.
Results: Rg1 alleviated cardiac hypertrophy and fibrosis, and improved cardiac decompensation inducedby AAC in rat myocardial tissue and cultured cardiomyocytes and cardiac fibroblasts. Importantly, Rg1treatment inhibited CaSR expression and increase of [Ca2þ]i, which similar to the CaSR inhibitor NPS2143.
In addition, Rg1 treatment inhibited CaN and TGF-b1 pathways activation. Mechanistic analysis showedthat the CaSR agonist GdCl3 could not further increase the [Ca2þ]i and CaN pathway related proteinexpression induced by mechanical stretching in cultured cardiomyocytes. CsA, an inhibitor of CaN,inhibited cardiac hypertrophy, cardiac fibrosis, [Ca2þ]i and CaN signaling but had no effect on CaSRexpression.
Conclusion: The activation of CaN pathway and the increase of [Ca2þ]i mediated by CaSR are involved incardiac hypertrophy and fibrosis, that may be the target of cardioprotection of Rg1 against myocardialinjury.

참고문헌 (Reference)

• 1 Calaghan SC, "The role of calcium in the response of cardiac muscle to stretch" 71 : 59-90, 1999
• 2 Zhang YJ, "The ginsenoside Rg1 prevents transverse aortic constrictioninduced left ventricular hypertrophy and cardiac dysfunction by inhibiting fibrosis and enhancing angiogenesis" 62 : 50-57, 2013
• 3 Saygili E, "The angiotensin-calcineurin-NFAT pathway mediates stretch-induced up-regulation of matrix metalloproteinases-2/-9 in atrial myocytes" 104 : 435-448, 2009
• 4 Finsen AV, "Syndecan-4 is essential for development of concentric myocardial hypertrophy via stretch-induced activation of the calcineurin-NFAT pathway" 6 : e28302-, 2011
• 5 Chen HH, "Stachydrine ameliorates pressure overload-induced diastolic heart failure by suppressing myocardial fibrosis" 9 : 4250-4260, 2017
• 6 Lu FH, "Role of the calcium-sensing receptor in cardiomyocyte apoptosis via the sarcoplasmic reticulum and mitochondrial death pathway in cardiac hypertrophy and heart failure" 31 : 728-743, 2013
• 7 Hong S, "Role of the calcium sensing receptor in cardiomyocyte apoptosis via mitochondrial dynamics in compensatory hypertrophied myocardium of spontaneously hypertensive rat" 487 : 728-733, 2017
• 8 Jiang WY, "Renal denervation ameliorates post-infarction cardiac remodeling in rats through dual regulation of oxidative stress in the heart and brain" 118 : 109243-, 2019
• 9 Wei WY, "Pioglitazone alleviates cardiac fibrosis and inhibits endothelial to mesenchymal transition induced by pressure overload" 45 : 26-36, 2018
• 10 Wang J, "Phenylephrine promotes cardiac fibroblast proliferation through calcineurin-NFAT pathway" 21 : 502-513, 2016
• 11 Glasenapp A, "Multimodality imaging of inflammation and ventricular remodeling in pressure overload heart failure" 2019
• 12 Zhou N, "Mechanical stress-evoked but angiotensin II-independent activation of angiotensin II type 1 receptor induces cardiac hypertrophy through calcineurin pathway" 397 : 263-269, 2010
• 13 Ruwhof C, "Mechanical stress stimulates phospholipase C activity and intracellular calcium ion levels in neonatal rat cardiomyocytes" 29 : 73-83, 2001
• 14 Zheng RH, "Liraglutide attenuates cardiac remodeling and improves heart function after abdominal aortic constriction through blocking angiotensin II type 1 receptor in rats" 13 : 2745-2757, 2019
• 15 Liu CJ, "Lipopolysaccharide induces cellular hypertrophy through calcineurin/NFAT-3 signaling pathway in H9c2 myocardiac cells" 313 : 167-178, 2008
• 16 Wang LN, "Involvement of calcium-sensing receptor in cardiac hypertrophy-induced by angiotensinII through calcineurin pathway in cultured neonatal rat cardiomyocytes" 369 : 584-589, 2008
• 17 Tang F, "Inhibition of TNF-alpha-mediated NF-kappaB activation by ginsenoside Rg1contributes the attenuation of cardiac hypertrophy induced by abdominal aorta coarctation" 68 : 257-264, 2016
• 18 Kumar S, "Hypoxiainduced mitogenic factor promotes cardiac hypertrophy via calciumdependent and hypoxia-inducible factor-1alpha mechanisms" 72 : 331-342, 2018
• 19 Park S, "Ginsenosides Rb1 and Rg1 suppress triglyceride accumulation in 3T3-L1 adipocytes and enhance beta-cell insulin secretion and viability in Min6 cells via PKA-dependent pathways" 72 : 2815-2823, 2008
• 20 Xu TZ, "Ginsenoside Rg1protects against H2O2induced neuronal damage due to inhibition of the NLRP1 inflammasome signalling pathway in hippocampal neurons in vitro" 43 : 717-726, 2019
• 21 Xu Y, "Ginsenoside Rg1 protects against non-alcoholic fatty liver disease by ameliorating lipid peroxidation, endoplasmic reticulum stress, and inflammasome activation" 41 : 1638-1644, 2018
• 22 Xu Z, "Ginsenoside Rg1 protects H9c2 cells against nutritional stress-induced injury via aldolase/AMPK/PINK1 signalling" 120 : 18388-18397, 2019
• 23 Xu ZM, "Ginsenoside Rg1 prevents doxorubicininduced cardiotoxicity through the inhibition of autophagy and endoplasmic reticulum stress in mice" 19 : 2018
• 24 Fan X, "Ginsenoside Rg1 attenuates hepatic insulin resistance induced by high-fat and high-sugar by inhibiting inflammation" 854 : 247-255, 2019
• 25 Li L, "Ginsenoside Rg1 ameliorates rat myocardial ischemia-reperfusion injury by modulating energy metabolism pathways" 9 : 78-, 2018
• 26 Qin Q, "Ginsenoside Rg1 ameliorates cardiac oxidative stress and inflammation in streptozotocin-induced diabetic rats" 12 : 1091-1103, 2019
• 27 Huang Y, "Ginsenoside Rg1 activates dendritic cells and acts as a vaccine adjuvant inducing protective cellular responses against lymphomas" 36 : 1168-1177, 2017
• 28 Spurr NK, "Genetics of calcium-sensing–regulation of calcium levels in the body" 3 : 291-294, 2003
• 29 Li X, "Epoxyeicosatrienoic acid prevents maladaptiveremodeling in pressure overload by targeting calcineurin/NFAT and Smad-7" 2019 : 111716-, 2019
• 30 Tsai CY, "E2/ER beta inhibit ISO-induced cardiac cellular hypertrophy by suppressing Ca2þ-calcineurin signaling" 12 : e0184153-, 2017
• 31 Liu L, "Calhex(2)(3)(1)ameliorates cardiac hypertrophy by inhibiting cellular autophagy in vivo and in vitro" 36 : 1597-1612, 2015
• 32 Jiang CM, "Calciumsensing receptors induce apoptosis in cultured neonatal rat ventricular cardiomyocytes during simulated ischemia/reperfusion" 32 : 792-800, 2008
• 33 Yuan H, "Calciumsensing receptor promotes high glucoseinduced myocardial fibrosis via upregulation of the TGFbeta1/Smads pathway in cardiac fibroblasts" 20 : 1093-1102, 2019
• 34 Lu F, "Calcium-sensing receptors induce apoptosis in rat cardiomyocytes via the endo(sarco)plasmic reticulum pathway during hypoxia/reoxygenation" 106 : 396-405, 2010
• 35 Sun YH, "Calcium-sensing receptor induces rat neonatal ventricular cardiomyocyte apoptosis" 350 : 942-948, 2006
• 36 Zheng H, "Calcium-sensing receptor activating phosphorylation of PKCdelta translocation on mitochondria to induce cardiomyocyte apoptosis during ischemia/reperfusion" 358 : 335-343, 2011
• 37 Lu M, "Calcium sensing receptor-related pathway contributes to cardiac injury and the mechanism of astragaloside IV on cardioprotection" 9 : 1163-, 2018
• 38 Tfelt-Hansen J, "Calcium receptor is functionally expressed in rat neonatal ventricular cardiomyocytes" 290 : H1165-H1171, 2006
• 39 Molostvov G, "Arterial expression of the calcium-sensing receptor is maintained by physiological pulsation and protects against calcification" 10 : e0138833-, 2015
• 40 Chi J, "Activation of calcium-sensing receptor-mediated autophagy in angiotensinII-induced cardiac fibrosis in vitro" 497 : 571-576, 2018
• 41 Tornatore TF, "A role for focal adhesion kinase in cardiac mitochondrial biogenesis induced by mechanical stress" 300 : H902-12, 2011