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Cross-Talk Between Mechanosensitive Ion Channels and Calcium Regulatory Proteins in Cardiovascular Health and Disease

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Cross-Talk Between Mechanosensitive Ion Channels and Calcium Regulatory Proteins in Cardiovascular Health and Disease International Journal of Molecular Sciences Review Cross-Talk between Mechanosensitive Ion Channels and Calcium Regulatory Proteins in Cardiovascular Health and Disease Yaping Wang 1, Jian Shi 2,* and Xiaoyong Tong 1,* 1 Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China; [email protected] 2 Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds LS2 9JT, UK * Correspondence: [email protected] (J.S.); [email protected] (X.T.) Abstract: Mechanosensitive ion channels are widely expressed in the cardiovascular system. They translate mechanical forces including shear stress and stretch into biological signals. The most prominent biological signal through which the cardiovascular physiological activity is initiated or maintained are intracellular calcium ions (Ca2+). Growing evidence show that the Ca2+ entry mediated by mechanosensitive ion channels is also precisely regulated by a variety of key proteins which are distributed in the cell membrane or endoplasmic reticulum. Recent studies have revealed that mechanosensitive ion channels can even physically interact with Ca2+ regulatory proteins and these interactions have wide implications for physiology and pathophysiology. Therefore, this paper 2+ reviews the cross-talk between mechanosensitive ion channels and some key Ca regulatory proteins in the maintenance of calcium homeostasis and its relevance to cardiovascular health and disease. Citation: Wang, Y.; Shi, J.; Tong, X. 2+ Cross-Talk between Keywords: mechanosensitive ion channels; Piezo channels; TRP channels; Ca ; NCX; Orai; STIM; Mechanosensitive Ion Channels and IP3R; SERCA; cardiovascular disease Calcium Regulatory Proteins in Cardiovascular Health and Disease. Int. J. Mol. Sci. 2021, 22, 8782. https://doi.org/10.3390/ 1. Introduction ijms22168782 Despite decades of efforts, cardiovascular disease is still the number one killer in the world. The latest data show that one in six elderly people dies of cardiovascular disease. Academic Editor: Pietro Campiglia In 2019, ischemic heart disease and stroke were reported to be the leading causes for disability in the age groups of 50–74 and 75 years or above [1]. As a dominant second Received: 28 July 2021 messenger, Ca2+ plays an important role in the cardiovascular health and diseases. For Accepted: 14 August 2021 Published: 16 August 2021 example, dietary calcium supplement and its retention reduce cardiovascular response to sodium stress in Black people [2]. There are still some controversies over the cardiovascular 2+ 2+ Publisher’s Note: MDPI stays neutral effects of high Ca intake in the diet, and whether the relationship between Ca intake 2+ with regard to jurisdictional claims in and cardiovascular disease risk is J- or U-shape [3]. Ca is pivotal in maintaining the published maps and institutional affil- functions of endothelial cells, smooth muscle cells (SMCs) and cardiomyocytes. It controls iations. the contraction or relaxation of arteries and heart and regulates blood pressure and cardiac functions [4–7]. The cell membrane controls the balance between intracellular and extracellular Ca2+ via various proteins, and thus maintains Ca2+ homeostasis. Plasma membrane Ca2+ ATPase (PMCA), voltage-gated calcium channel (VGCC), Na+/Ca2+ exchanger (NCX), and Orai Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. have been identified as the main calcium regulatory proteins on the cell membrane [8–11]. 2+ This article is an open access article Endoplasmic reticulum (ER) as an important Ca reservoir in the cell also contains some distributed under the terms and calcium regulatory proteins. Such proteins in the ER include stromal interaction molecules conditions of the Creative Commons (STIM), inositol 1,4,5-trisphosphate receptor (IP3R), and sarco/endoplasmic reticulum Attribution (CC BY) license (https:// calcium-ATPase (SERCA). All these proteins are critical in controlling cell functions, such as creativecommons.org/licenses/by/ growth, migration, apoptosis, and metabolism [12–14]. As a general feedback mechanism, 2+ 2+ 4.0/). these key Ca regulatory proteins are also regulated by intracellular Ca level. Int. J. Mol. Sci. 2021, 22, 8782. https://doi.org/10.3390/ijms22168782 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 18 sarco/endoplasmic reticulum calcium-ATPase (SERCA). All these proteins are critical in controlling cell functions, such as growth, migration, apoptosis, and metabolism [12,13,14]. As a general feedback mechanism, these key Ca2+ regulatory proteins are also regulated by intracellular Ca2+ level. Int. J. Mol. Sci. 2021, 22, 8782 Mechanical forces are crucial for cardiovascular functions and therefore2 of 18the discoveries of mechanosensitive ion channels represent a major breakthrough in understanding cardiovascular mechanobiology. In particular, the endothelium in the cardiovascularMechanical system forces is are subjected crucial for to cardiovascularregular mechanical functions stimulus andtherefore evoked by the blood discover- flow. Theies ofdiscovered mechanosensitive mechanosensitive ion channels ion represent channels a including major breakthrough Piezo channels in understanding and transient receptorcardiovascular potential mechanobiology. (TRP) channels In can particular, conduct thethe endotheliumentry of cationic in the ions, cardiovascular particularly sys-Ca2+, intem response is subjected to the to stimulus regular mechanicalfrom shear stimulusstress of evokedblood flow by blood[15,16]. flow. Both The Piezo discovered and TRP channelsmechanosensitive are closely ion channelslinked to including the development Piezo channels of cardiovascular and transient receptordisease. potential In some 2+ cardiovascular(TRP) channels candiseases, conduct such the as entry hypertension, of cationic ions, atherosclerosis, particularly Caor aneurysmal, in response plaques, to the alteredstimulus mechanical from shear stress stress which of blood can flow directly [15,16 activate]. Both Piezomechanosensitive and TRP channels ion channels are closely has beenlinked reported to the development [17]. of cardiovascular disease. In some cardiovascular diseases, such as hypertension,Ca2+ regulatory atherosclerosis, proteins sensitize or aneurysmal any subtle plaques, change altered of mechanicalintracellular stress Ca2+ which. It has can directly activate mechanosensitive ion channels has been reported [17]. emerged that these proteins can cross-talk to mechanosensitive ion channels (Figure 1) Ca2+ regulatory proteins sensitize any subtle change of intracellular Ca2+. It has and such cross-talk can even take place with direct and physical interactions between emerged that these proteins can cross-talk to mechanosensitive ion channels (Figure1) and them, such as Piezo and SERCA [18]. This paper reviews the cross-talk between such cross-talk can even take place with direct and physical interactions between them, mechanosensitive ion channels and some key Ca2+ regulatory proteins in the regulation of such as Piezo and SERCA [18]. This paper reviews the cross-talk between mechanosensitive Ca2+ homeostasis from the perspective of cardiovascular health and disease. In-depth ion channels and some key Ca2+ regulatory proteins in the regulation of Ca2+ homeostasis understandingfrom the perspective of the of structure, cardiovascular function, health and and cross-talk disease. of In-depth these proteins understanding will help of us the to unravelstructure, the function, pathogenesis and cross-talk of cardiovascular of these proteins disease will and help further us to develop unravel thenovel pathogenesis therapeutic strategies.of cardiovascular It is noted disease that the and cross-talk further develop or interaction noveltherapeutic between mechanical strategies. ion It ischannels, noted PMCA,that the VGCC cross-talk in cardiovascular or interaction betweensystem awaits mechanical further ion investigation channels, PMCA, and hence VGCC is innot reviewedcardiovascular in this system paper. awaits further investigation and hence is not reviewed in this paper. 2+ 2+ FigureFigure 1. CaCa2+ linkslinks Ca Ca2+ regulatoryregulatory proteins proteins with mechanosensitivemechanosensitive ionion channelschannels to to regulate regulate cardiovascularcardiovascular health and diseases.diseases. TheThe mechanicalmechanical stressstress generated generated in in either either cardiovascular cardiovascular health health oror disease directly stimulatesstimulates mechanosensitivemechanosensitive ion ion channels channels and and induces induces Ca Ca2+ 2+entry. entry. Then Then the the Ca Ca2+ 2+ regulatoryregulatory proteins sensingsensing thethe changeschanges of of Ca Ca2+2+ cross-talkcross-talk toto oror interact interact with with mechanosensitive mechanosensitive ion ion channels,channels, which contributes toto thethe developmentdevelopment of of cardiovascular cardiovascular disease disease or or health. health. 2.2. Ca Ca2+2+ RegulatoryRegulatory Proteins Proteins in in Cardiovascular Cardiovascular System 2.1.2.1. NCX NCX NCXNCX mainly works inin thethe forwardforward mode,mode, whichwhich uses uses the the electrochemical electrochemical gradient gradient + 2+ 2+ drivendriven by Na+ to expel CaCa2+ from cellscells inin orderorder toto maintainmaintain the the concentration concentration of of Ca Ca2+ + 2+ requiredrequired for physiologicalphysiological
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