The Potential of Berberine to Target Telocytes in Rabbit Heart

Abstract

A brand-new class of interstitial cells, called telocytes, has been detected in the heart. Telocytes can connect and transmit signals to almost all cardiomyocytes; this is highly interrelated with the occurrence and development of heart diseases. Modern studies have shown that berberine has a therapeutic effect on cardiovascular health. However, berberineʼs mechanism of action on the cardiovascular system through cardiac telocytes is unclear. Interestingly, 5 µm of berberine remarkably decreased the concentration of intracellular calcium and membrane depolarization in cultured telocytes, upregulated the expression of CX43 and β-catenin, and downregulated the expressions of TRPV4 and TRPV1. Here, telocytes were identified in the vascular adventitia and intima, endocardium, myocardium, adventitia, and heart valves. Moreover, telocytes were broadly dispersed around cardiac vessels and interacted directly through gap junctions and indirectly through extracellular vesicles. Together, cardiac telocytes interact with berberine and then deliver drug information to the heart. Telocytes may be an essential cellular target for drug therapy of the cardiovascular system.

Key words

cardiac telocytes - berberine - Ca²⁺ - CX43

Publication History

Received: 24 April 2023

Accepted after revision: 10 September 2023

Accepted Manuscript online:
15 September 2023

Article published online:
17 October 2023

• References

• 1 Popescu LM, Faussone-Pellegrini MS. TELOCYTES – a case of serendipity: The winding way from Interstitial Cells of Cajal (ICC), via Interstitial Cajal-Like Cells (ICLC) to TELOCYTES. J Cell Mol Med 2010; 14: 729-740
• 2 Gherghiceanu M, Popescu LM. Cardiac telocytes – their junctions and functional implications. Cell Tissue Res 2012; 348: 265-279
• 3 Mu YP, Lin DC, Yan FR, Jiao HX, Gui LX, Lin MJ. Alterations in Caveolin-1 expression and receptor-operated Ca²⁺ entry in the aortas of rats with pulmonary hypertension. Cell Physiol Biochem 2016; 39: 438-452
• 4 Cretoiu D, Roatesi S, Bica I, Plesca C, Stefan A, Bajenaru O, Condrat CE, Cretoiu SM. Simulation and modeling of telocytes behavior in signaling and intercellular communication processes. Int J Mol Sci 2020; 21: 2615
• 5 Klein M, Csöbönyeiová M, Žiaran S, Danišovič Ľ, Varga I. Cardiac telocytes 16 years on-what have we learned so far, and how close are we to routine application of the knowledge in cardiovascular regenerative medicine?. Int J Mol Sci 2021; 22: 10942
• 6 Aschacher T, Schmidt K, Aschacher O, Eichmair E, Baranyi U, Winkler B, Grabenwoeger M, Spittler A, Enzmann F, Messner B, Riebandt J, Laufer G, Bergmann M, Ehrlich M. Telocytes in the human ascending aorta: Characterization and exosome-related KLF-4/VEGF-A expression. J Cell Mol Med 2021; 25: 9697-9709
• 7 Liao Z, Chen Y, Duan C, Zhu K, Huang R, Zhao H, Hintze M, Pu Q, Yuan Z, Lv L, Chen H, Lai B, Feng S, Qi X, Cai D. Cardiac telocytes inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21–5 p-targeted cdip1 silencing to improve angiogenesis following myocardial infarction. Theranostics 2021; 11: 268-291
• 8 Smythies J, Edelstein L. Telocytes, exosomes, gap junctions and the cytoskeleton: the makings of a primitive nervous system?. Front Cell Neurosci 2014; 7: 278
• 9 Kostin S. Cardiac telocytes in normal and diseased hearts. Semin Cell Dev Biol 2016; 55: 22-30
• 10 Richter M, Kostin S. The failing human heart is characterized by decreased numbers of telocytes as result of apoptosis and altered extracellular matrix composition. J Cell Mol Med 2015; 19: 2597-2606
• 11 DeSimone CV, McLeod CJ, Gomez Pinilla PJ, Beyder A, Farrugia G, Asirvatham SJ, Kapa S. Telocytes express ANO-1-encoded chloride channels in canine ventricular myocardium. J Arrhythm 2019; 35: 515-521
• 12 Liskova YV, Stadnikov AA, Salikova SP. [The role of telocytes in myocardial remodeling and the development of cardiovascular complications in patients with chronic heart failure after coronary artery bypass grafting]. Kardiologiia 2018; 58: 29-37
• 13 Thomford NE, Senthebane DA, Rowe A, Munro D, Seele P, Maroyi A, Dzobo K. Natural products for drug discovery in the 21st century: Innovations for novel drug discovery. Int J Mol Sci 2018; 19: 1578
• 14 Mishra BB, Tiwari VK. Natural products: An evolving role in future drug discovery. Eur J Med Chem 2011; 46: 4769-4807
• 15 Feng X, Sureda A, Jafari S, Memariani Z, Tewari D, Annunziata G, Barrea L, Hassan STS, Šmejkal K, Malaník M, Sychrová A, Barreca D, Ziberna L, Mahomoodally MF, Zengin G, Xu S, Nabavi SM, Shen AZ. Berberine in cardiovascular and metabolic diseases: From mechanisms to therapeutics. Theranostics 2019; 9: 1923-1951
• 16 Marin-Neto JA, Maciel BC, Secches AL, Gallo Júnior L. Cardiovascular effects of berberine in patients with severe congestive heart failure. Clin Cardiol 1988; 11: 253
• 17 Guo Z, Sun H, Zhang H, Zhang Y. Anti-hypertensive and renoprotective effects of berberine in spontaneously hypertensive rats. Clin Exp Hypertens 2015; 37: 332-339
• 18 Wang LH, Yu CH, Fu Y, Li Q, Sun YQ. Berberine elicits anti-arrhythmic effects via IK1/Kir2.1 in the rat type 2 diabetic myocardial infarction model. Phytother Res 2011; 25: 33-37
• 19 Zhang XD, Ren HM, Liu L. Effects of different dose berberine on hemodynamic parameters and [Ca²⁺]i of cardiac myocytes of diastolic heart failure rat model. Zhongguo Zhong Yao Za Zhi 2008; 33: 818-821
• 20 Bril A. Transporteurs ioniques dans les pathologies cardiovasculaires: Contrôle du pH ou régulation de la concentration calcique intracellulaire [Ion transporters and cardiovascular diseases: pH control or modulation of intracellular calcium concentration]. Ann Cardiol Angeiol (Paris) 2003; 52: 41-51
• 21 Zhang M, Feng LJ, Li JN, Chen L. Therapeutic potential and mechanisms of berberine in cardiovascular disease. Curr Pharmacol Rep 2016; 2: 281-292
• 22 Wang J, Guo T, Peng QS, Yue SW, Wang SX. Berberine via suppression of transient receptor potential vanilloid 4 channel improves vascular stiffness in mice. J Cell Mol Med 2015; 19: 2607-2616
• 23 Bai XB, Wu RZ, Zhang Y, Liang CH, Shi YH, Zhang YX, Ding BT, Tarique I, Yang P, Chen QS. Tissue micro-channels formed by collagen fibers and their internal components: Cellular evidence of proposed meridian conduits in vertebrate skin. Microsc Microanal 2020; 26: 1069-1075
• 24 Shi YH, Wu RZ, Zhang Y, Bai XB, Tarique I, Liang CH, Yang P, Chen QS. Telocytes in different organs of vertebrates: Potential essence cells of the meridian in Chinese traditional medicine. Microsc Microanal 2020; 26: 575-588
• 25 Wang LH, Li XL, Li Q, Fu Y, Yu HJ, Sun YQ, Zhang L, Shan HL. Berberine alleviates ischemic arrhythmias via recovering depressed I(to) and I(Ca) currents in diabetic rats. Phytomedicine 2012; 19: 206-210
• 26 Ribeiro-Oliveira R, Martins ZE, Faria MÂ, Sousa JB, Ferreira IMPLVO, Diniz C. Protein hydrolysates from brewing by-products as natural alternatives to ACE-inhibitory drugs for hypertension management. Life (Basel) 2022; 12: 1554
• 27 Das PN, Mehrotra P, Mishra A, Bairagi N, Chatterjee S. Calcium dynamics in cardiac excitatory and non-excitatory cells and the role of gap junction. Math Biosci 2017; 289: 51-68
• 28 Dakshinamurti S, Geiger J, Dakshinamurti K. Control of intracellular calcium levels. Nutrients and cell signaling 2005; 589-620 ref 119
• 29 Sen B, Xie Z, Howard S, Styner M, van Wijnen AJ, Uzer G, Rubin J. Mechanically induced nuclear shuttling of β-catenin requires co-transfer of actin. Stem Cells 2022; 40: 423-434
• 30 Li VS, Ng SS, Boersema PJ, Low TY, Karthaus WR, Gerlach JP, Mohammed S, Heck AJ, Maurice MM, Mahmoudi T, Clevers H. Wnt signaling through inhibition of β-catenin degradation in an intact Axin1 complex. Cell 2012; 149: 1245-1256
• 31 Chaigne S, Dupuis S, Constantin M, Desplantez T. P117Co-expressed cardiac connexins: dependence on the Cx43:Cx40 ratio in regulating the gap junction channel make-up and electrical properties. Cardiovasc Res 2014; 103 (Suppl. 01) S20
• 32 Beyer EC, Hwan Seul K, Larson DM. Cardiovascular Gap Junction Proteins: Molecular Characterization and Biochemical Regulation. Heart Cell Communication in Health and Disease 1998; 45-72
• 33 Severs NJ, Coppen SR, Dupont E, Yeh HI, Ko YS, Matsushita T. Gap junction alterations in human cardiac disease. Cardiovasc Res 2004; 62: 368-377
• 34 Severs NJ, Dupont E, Coppen SR, Halliday D, Inett E, Baylis D, Rothery S. Remodelling of gap junctions and connexin expression in heart disease. Biochim Biophys Acta 2004; 1662: 138-148
• 35 Shim W. Myocardial telocytes: A new player in electric circuitry of the heart. Adv Exp Med Biol 2016; 913: 241-251
• 36 Cretoiu SM, Radu BM, Banciu A, Banciu DD, Cretoiu D, Ceafalan LC, Popescu LM. Isolated human uterine telocytes: Immunocytochemistry and electrophysiology of T-type calcium channels. Histochem Cell Biol 2015; 143: 83-94
• 37 Lupiński SŁ, Schlicker E, Pędzińska-Betiuk A, Malinowska B. Acute myocardial ischemia enhances the vanilloid TRPV1 and serotonin 5-HT3 receptor-mediated Bezold-Jarisch reflex in rats. Pharmacol Rep 2011; 63: 1450-1459
• 38 Chen M, Li X. Role of TRPV4 channel in vasodilation and neovascularization. Microcirculation 2021; 28: e12703