Regulated vascular smooth muscle cell death in vascular diseases

Abstract

Regulated cell death (RCD) is a complex process that involves several cell types and plays a crucial role in vascular diseases. Vascular smooth muscle cells (VSMCs) are the predominant elements of the medial layer of blood vessels, and their regulated death contributes to the pathogenesis of vascular diseases. The types of regulated VSMC death include apoptosis, necroptosis, pyroptosis, ferroptosis, parthanatos, and autophagy-dependent cell death (ADCD). In this review, we summarize the current evidence of regulated VSMC death pathways in major vascular diseases, such as atherosclerosis, vascular calcification, aortic aneurysm and dissection, hypertension, pulmonary arterial hypertension, neointimal hyperplasia, and inherited vascular diseases. All forms of RCD constitute a single, coordinated cell death system in which one pathway can compensate for another during disease progression. Pharmacologically targeting RCD pathways has potential for slowing and reversing disease progression, but challenges remain. A better understanding of the role of regulated VSMC death in vascular diseases and the underlying mechanisms may lead to novel pharmacological developments and help clinicians address the residual cardiovascular risk in patients with cardiovascular diseases.

References

[1] KerrJF, WyllieAH, CurrieAR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26(4):239-257.

[2] HollerN, ZaruR, MicheauO, et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol. 2000;1(6):489-495.

[3] WallVZ, Bornfeldt KE. Arterial smooth muscle. Arterioscler Thromb Vasc Biol. 2014;34(10):2175-2179.

[4] OwensGK, KumarMS, WamhoffBR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev. 2004;84(3):767-801.

[5] XieC, Ritchie RP, HuangH, ZhangJ, ChenYE. Smooth muscle cell differentiation in vitro: models and underlying molecular mechanisms. Arterioscler Thromb Vasc Biol. 2011;31(7):1485-1494.

[6] KockxMM, HermanAG. Apoptosis in atherosclerosis: beneficial or detrimental? Cardiovasc Res. 2000;45(3):736-746.

[7] FlynnPD, ByrneCD, BaglinTP, Weissberg PL, BennettMR. Thrombin generation by apoptotic vascular smooth muscle cells. Blood. 1997;89(12):4378-4384.

[8] ClarkeMC, FiggN, MaguireJJ, et al. Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis. Nat Med. 2006;12(9):1075-1080.

[9] ClarkeMC, Littlewood TD, FiggN, et al. Chronic apoptosis of vascular smooth muscle cells accelerates atherosclerosis and promotes calcification and medial degeneration. Circ Res. 2008;102(12):1529-1538.

[10] MilewiczDM, Ramirez F. Therapies for thoracic aortic aneurysms and acute aortic dissections. Arterioscler Thromb Vasc Biol. 2019;39(2):126-136.

[11] DurduS, DenizGC, BalciD, et al. Apoptotic vascular smooth muscle cell depletion via BCL2 family of proteins in human ascending aortic aneurysm and dissection. Cardiovasc Ther. 2012;30(6):308-316.

[12] SigalaF, Papalambros E, KotsinasA, et al. Relationship between iNOS expression and aortic cell proliferation and apoptosis in an elastase-induced model of aorta aneurysm and the effect of 1400 W administration. Surgery. 2005;137(4):447-456.

[13] EmrichFC, Okamura H, DalalAR, et al. Enhanced caspase activity contributes to aortic wall remodeling and early aneurysm development in a murine model of Marfan syndrome. Arterioscler Thromb Vasc Biol. 2015;35(1):146-154.

[14] CowanKN, LeungWC, MarC, Bhattacharjee R, ZhuY, RabinovitchM. Caspases from apoptotic myocytes degrade extracellular matrix: a novel remodeling paradigm. FASEB J. 2005;19(13):1848-1850.

[15] von WnuckLK, KeulP, FerriN, et al. Integrin-mediated transcriptional activation of inhibitor of apoptosis proteins protects smooth muscle cells against apoptosis induced by degraded collagen. Circ Res. 2006;98(12):1490-1497.

[16] PerlmanH, Maillard L, KrasinskiK, WalshK. Evidence for the rapid onset of apoptosis in medial smooth muscle cells after balloon injury. Circulation. 1997;95(4):981-987.

[17] WeiGL, Krasinski K, KearneyM, IsnerJM, WalshK, AndrésV. Temporally and spatially coordinated expression of cell cycle regulatory factors after angioplasty. Circ Res. 1997;80(3):418-426.

[18] Bochaton-PiallatML, Gabbiani F, RedardM, DesmoulièreA, Gabbiani G. Apoptosis participates in cellularity regulation during rat aortic intimal thickening. Am J Pathol. 1995;146(5):1059-1064.

[19] ClowesAW, ReidyMA, ClowesMM. Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium. Laboratory Investigation. 1983;49(3):327-333.

[20] WalshK, SmithRC, KimHS. Vascular cell apoptosis in remodeling, restenosis, and plaque rupture. Circ Res. 2000;87(3):184-188.

[21] ClowesAW, ClowesMM. Kinetics of cellular proliferation after arterial injury. II. Inhibition of smooth muscle growth by heparin. Laboratory Investigation. 1985;52(6):611-616.

[22] BeoharN, Flaherty JD, DavidsonCJ, et al. Antirestenotic effects of a locally delivered caspase inhibitor in a balloon injury model. Circulation. 2004;109(1):108-113.

[23] MesserliFH, Williams B, RitzE. Essential hypertension. Lancet. 2007;370(9587):591-603.

[24] HametP, Richard L, DamTV, et al. Apoptosis in target organs of hypertension. Hypertension. 1995;26(4):642-648.

[25] DíezJ, Fortuño MA, ZalbaG, et al. Altered regulation of smooth muscle cell proliferation and apoptosis in small arteries of spontaneously hypertensive rats. Eur Heart J. 1998;19(Suppl G):G29-G33.

[26] HametP. Proliferation and apoptosis of vascular smooth muscle in hypertension. Curr Opin Nephrol Hypertens. 1995;4(1):1-7.

[27] HametP, deBlois D, DamTV, et al. Apoptosis and vascular wall remodeling in hypertension. Can J Physiol Pharmacol. 1996;74(7):850-861.

[28] deBloisD, TeaBS, ThanVD, Tremblay J, HametP. Smooth muscle apoptosis during vascular regression in spontaneously hypertensive rats. Hypertension. 1997;29(1 Pt 2):340-349.

[29] DíezJ, PanizoA, HernándezM, PardoJ. Is the regulation of apoptosis altered in smooth muscle cells of adult spontaneously hypertensive rats? Hypertension. 1997;29(3):776-780.

[30] TeaBS, Der Sarkissian S, TouyzRM, HametP, deBlois D. Proapoptotic and growth-inhibitory role of angiotensin II type 2 receptor in vascular smooth muscle cells of spontaneously hypertensive rats in vivo. Hypertension. 2000;35(5):1069-1073.

[31] MarchandEL, Der Sarkissian S, HametP, deBloisD. Caspase-dependent cell death mediates the early phase of aortic hypertrophy regression in losartan-treated spontaneously hypertensive rats. Circ Res. 2003;92(7):777-784.

[32] SharifiAM, Schiffrin EL. Apoptosis in vasculature of spontaneously hypertensive rats: effect of an angiotensin converting enzyme inhibitor and a calcium channel antagonist. Am J Hypertens. 1998;11(9):1108-1116.

[33] HassounPM. Pulmonary arterial hypertension. N Engl J Med. 2021;385(25):2361-2376.

[34] MandegarM, FungYC, HuangW, Remillard CV, RubinLJ, YuanJX. Cellular and molecular mechanisms of pulmonary vascular remodeling: role in the development of pulmonary hypertension. Microvasc Res. 2004;68(2):75-103.

[35] HuangJB, LiuYL, SunPW, Lv XD, BoK, FanXM. Novel strategy for treatment of pulmonary arterial hypertension: enhancement of apoptosis. Lung. 2010;188(3):179-189.

[36] UngvariZ, Tarantini S, DonatoAJ, GalvanV, Csiszar A. Mechanisms of vascular aging. Circ Res. 2018;123(7):849-867.

[37] VictorelliS, Salmonowicz H, ChapmanJ, et al. Apoptotic stress causes mtDNA release during senescence and drives the SASP. Nature. 2023;622(7983):627-636.

[38] GrootaertMOJ, MoulisM, RothL, et al. Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis. Cardiovasc Res. 2018;114(4):622-634.

[39] BennettMR, Macdonald K, ChanSW, BoyleJJ, Weissberg PL. Cooperative interactions between RB and p53 regulate cell proliferation, cell senescence, and apoptosis in human vascular smooth muscle cells from atherosclerotic plaques. Circ Res. 1998;82(6):704-712.

[40] YosefR, PilpelN, Tokarsky-AmielR, et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun. 2016;7:11190.

[41] KarunakaranD, Geoffrion M, WeiL, et al. Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis. Sci Adv. 2016;2(7):e1600224.

[42] MengL, JinW, WangX. RIP3-mediated necrotic cell death accelerates systematic inflammation and mortality. Proc Natl Acad Sci U S A. 2015;112(35):11007-11012.

[43] LinJ, LiH, YangM, et al. A role of RIP3-mediated macrophage necrosis in atherosclerosis development. Cell Rep. 2013;3(1):200-210.

[44] RasheedA, Robichaud S, NguyenMA, et al. Loss of MLKL (mixed lineage kinase domain-like protein) decreases necrotic core but increases macrophage lipid accumulation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2020;40(5):1155-1167.

[45] DublandJA, Francis GA. So much cholesterol: the unrecognized importance of smooth muscle cells in atherosclerotic foam cell formation. Curr Opin Lipidol. 2016;27(2):155-161.

[46] ColijnS, Muthukumar V, XieJ, GaoS, Griffin CT. Cell-specific and athero-protective roles for RIPK3 in a murine model of atherosclerosis. Dis Model Mech. 2020;13(1):dmm041961.

[47] KarunakaranD, NguyenMA, GeoffrionM, et al. RIPK1 expression associates with inflammation in early atherosclerosis in humans and can be therapeutically silenced to reduce NF-κB activation and atherogenesis in mice. Circulation. 2021;143(2):163-177.

[48] WangQ, LiuZ, RenJ, MorganS, AssaC, Liu B. Receptor-interacting protein kinase 3 contributes to abdominal aortic aneurysms via smooth muscle cell necrosis and inflammation. Circ Res. 2015;116(4):600-611.

[49] LiK, ZhangD, ZhaiS, Wu H, LiuH. METTL3-METTL14 complex induces necroptosis and inflammation of vascular smooth muscle cells via promoting N6 methyladenosine mRNA methylation of receptor-interacting protein 3 in abdominal aortic aneurysms. J Cell Commun Signal. 2023;17(3):897-914.

[50] ZhouT, DeRooE, YangH, et al. MLKL and CaMKII are involved in RIPK3-mediated smooth muscle cell necroptosis. Cells. 2021;10(9):2397.

[51] WangQ, ZhouT, LiuZ, et al. Inhibition of receptor-interacting protein kinase 1 with Necrostatin-1s ameliorates disease progression in elastase-induced mouse abdominal aortic aneurysm model. Sci Rep. 2017;7:42159.

[52] ZhouT, WangQ, PhanN, et al. Identification of a novel class of RIP1/RIP3 dual inhibitors that impede cell death and inflammation in mouse abdominal aortic aneurysm models. Cell Death Dis. 2019;10(3):226.

[53] DingY, WangY, CaiY, et al. IL-37 expression in patients with abdominal aortic aneurysm and its role in the necroptosis of vascular smooth muscle cells. Oxid Med Cell Longev. 2022;2022:1806513.

[54] DuewellP, KonoH, RaynerKJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464(7293):1357-1361.

[55] LeeJ, WanJ, LeeL, PengC, XieH, LeeC. Study of the NLRP3 inflammasome component genes and downstream cytokines in patients with type 2 diabetes mellitus with carotid atherosclerosis. Lipids Health Dis. 2017;16(1):217.

[56] GrebeA, HossF, LatzE. NLRP3 Inflammasome and the IL-1 pathway in atherosclerosis. Circ Res. 2018;122(12):1722-1740.

[57] ZhouY, ZhouH, HuaL, et al. Verification of ferroptosis and pyroptosis and identification of PTGS2 as the hub gene in human coronary artery atherosclerosis. Free Radic Biol Med. 2021;171:55-68.

[58] LiY, NiuX, XuH, et al. VX-765 attenuates atherosclerosis in ApoE deficient mice by modulating VSMCs pyroptosis. Exp Cell Res. 2020;389(1):111847.

[59] WenC, YangX, YanZ, et al. Nalp3 inflammasome is activated and required for vascular smooth muscle cell calcification. Int J Cardiol. 2013;168(3):2242-2247.

[60] BurgerF, Baptista D, RothA, et al. NLRP3 inflammasome activation controls vascular smooth muscle cells phenotypic switch in atherosclerosis. Int J Mol Sci. 2021;23(1):340.

[61] HeX, BaiQ, ZhangX, Zhang L. MgCl(2) attenuates ox-LDL-induced vascular smooth muscle-derived foam cells pyroptosis by downregulating the TLR4/NF-κB signaling pathway. Biol Trace Elem Res. 2023;201:5242-5256.

[62] SharmaA, ChoiJSY, StefanovicN, et al. Specific NLRP3 inhibition protects against diabetes-associated atherosclerosis. Diabetes. 2021;70(3):772-787.

[63] PanJ, HanL, GuoJ, et al. AIM2 accelerates the atherosclerotic plaque progressions in ApoE-/-mice. Biochem Biophys Res Commun. 2018;498(3):487-494.

[64] GomezD, BaylisRA, DurginBG, et al. Interleukin-1β has atheroprotective effects in advanced atherosclerotic lesions of mice. Nat Med. 2018;24(9):1418-1429.

[65] WortmannM, Skorubskaya E, PetersAS, HakimiM, Böckler D, DihlmannS. Necrotic cell debris induces a NF-κB-driven inflammasome response in vascular smooth muscle cells derived from abdominal aortic aneurysms (AAA-SMC). Biochem Biophys Res Commun. 2019;511(2):343-349.

[66] WuD, RenP, ZhengY, et al. NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3)-caspase-1 inflammasome degrades contractile proteins: implications for aortic biomechanical dysfunction and aneurysm and dissection formation. Arterioscler Thromb Vasc Biol. 2017;37(4):694-706.

[67] RenP, WuD, AppelR, et al. Targeting the NLRP3 inflammasome with inhibitor MCC950 prevents aortic aneurysms and dissections in mice. J Am Heart Assoc. 2020;9(7):e014044.

[68] WortmannM, ArshadM, HakimiM, Böckler D, DihlmannS. Deficiency in Aim2 affects viability and calcification of vascular smooth muscle cells from murine aortas and angiotensin-II induced aortic aneurysms. Mol Med. 2020;26(1):87.

[69] HuJJ, LiuX, XiaS, et al. FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nat Immunol. 2020;21(7):736-745.

[70] LiaoF, WangL, WuZ, et al. Disulfiram protects against abdominal aortic aneurysm by ameliorating vascular smooth muscle cells pyroptosis. Cardiovasc Drugs Ther. 2022;37:1-14.

[71] GaoJ, ChenY, WangH, et al. Gasdermin D deficiency in vascular smooth muscle cells ameliorates abdominal aortic aneurysm through reducing putrescine synthesis. Adv Sci. 2023;10(5):e2204038.

[72] PangQ, WangP, PanY, et al. Irisin protects against vascular calcification by activating autophagy and inhibiting NLRP3-mediated vascular smooth muscle cell pyroptosis in chronic kidney disease. Cell Death Dis. 2022;13(3):283.

[73] ChangJF, KuoHL, LiuSH, et al. Translational medicine in uremic vascular calcification: scavenging ROS attenuates p-cresyl sulfate-activated caspase-1, NLRP3 inflammasome and eicosanoid inflammation in human arterial smooth muscle cells. Life. 2022;12(5):769.

[74] SchuchardtM, Herrmann J, HenkelC, BabicM, van der Giet M, TölleM. Long-term treatment of azathioprine in rats induces vessel mineralization. Biomedicine. 2021;9(3):327.

[75] XiaY, LiB, ZhangF, et al. Hydroxyapatite nanoparticles promote mitochondrial-based pyroptosis via activating calcium homeostasis and redox imbalance in vascular smooth muscle cells. Nanotechnology. 2022;33(27):275101.

[76] LiJP, WeiW, LiXX, XuM. Regulation of NLRP3 inflammasome by CD38 through cADPR-mediated Ca(2+) release in vascular smooth muscle cells in diabetic mice. Life Sci. 2020;255:117758.

[77] ZhangX, LiY, YangP, et al. Trimethylamine-N-oxide promotes vascular calcification through activation of NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome and NF-κB (nuclear factor κB) signals. Arterioscler Thromb Vasc Biol. 2020;40(3):751-765.

[78] HoLC, ChenYH, WuTY, et al. Phosphate burden induces vascular calcification through a NLRP3-caspase-1-mediated pyroptotic pathway. Life Sci. 2023;332:122123.

[79] XuZ, ChenZM, WuX, ZhangL, CaoY, ZhouP. Distinct molecular mechanisms underlying potassium efflux for NLRP3 inflammasome activation. Front Immunol. 2020;11:609441.

[80] DuanY, PengZ, ZhongS, et al. VX-765 ameliorates CKD VSMC calcification by regulating STAT3 activation. Eur J Pharmacol. 2023;945:175610.

[81] ChenA, LanZ, LiL, et al. Sodium-glucose cotransporter 2 inhibitor canagliflozin alleviates vascular calcification through suppression of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome. Cardiovasc Res. 2023;119(13):2368-2381.

[82] KunnasT, Määttä K, NikkariST. NLR family pyrin domain containing 3 (NLRP3) inflammasome gene polymorphism rs7512998 (C>T) predicts aging-related increase of blood pressure, the TAMRISK study. Immun Ageing. 2015;12:19.

[83] KrishnanSM, SobeyCG, LatzE, Mansell A, DrummondGR. IL-1β and IL-18:inflammatory markers or mediators of hypertension? Br J Pharmacol. 2014;171(24):5589-5602.

[84] SunHJ, RenXS, XiongXQ, et al. NLRP3 inflammasome activation contributes to VSMC phenotypic transformation and proliferation in hypertension. Cell Death Dis. 2017;8(10):e3074.

[85] QiHM, CaoQ, LiuQ. TLR4 regulates vascular smooth muscle cell proliferation in hypertension via modulation of the NLRP3 inflammasome. Am J Transl Res. 2021;13(1):314-325.

[86] HanY, SunHJ, TongY, et al. Curcumin attenuates migration of vascular smooth muscle cells via inhibiting NFκB-mediated NLRP3 expression in spontaneously hypertensive rats. J Nutr Biochem. 2019;72:108212.

[87] YinZ, ZhangJ, ZhaoM, et al. Maresin-1 ameliorates hypertensive vascular remodeling through its receptor LGR6. MedComm. 2024;5(3):e491.

[88] CauSB, Bruder-Nascimento A, SilvaMB, et al. Angiotensin-II activates vascular inflammasome and induces vascular damage. Vascul Pharmacol. 2021;139:106881.

[89] CeroFT, Hillestad V, SjaastadI, et al. Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol. 2015;309(4):L378-L387.

[90] UdjusC, CeroFT, HalvorsenB, et al. Caspase-1 induces smooth muscle cell growth in hypoxia-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2019;316(6):L999-l1012.

[91] HeS, MaC, ZhangL, et al. GLI1-mediated pulmonary artery smooth muscle cell pyroptosis contributes to hypoxia-induced pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2020;318(3):L472-l482.

[92] HuS, WangL, XuY, LiF, WangT. Disulfiram attenuates hypoxia-induced pulmonary hypertension by inhibiting GSDMD cleavage and pyroptosis in HPASMCs. Respir Res. 2022;23(1):353.

[93] VinchiF, PortoG, SimmelbauerA, et al. Atherosclerosis is aggravated by iron overload and ameliorated by dietary and pharmacological iron restriction. Eur Heart J. 2020;41(28):2681-2695.

[94] LeeTS, ShiaoMS, PanCC, Chau LY. Iron-deficient diet reduces atherosclerotic lesions in apoE-deficient mice. Circulation. 1999;99:1222-1229, 1229.

[95] MinqinR, Rajendran R, PanN, et al. The iron chelator desferrioxamine inhibits atherosclerotic lesion development and decreases lesion iron concentrations in the cholesterol-fed rabbit. Free Radic Biol Med. 2005;38(9):1206-1211.

[96] ZhangWJ, WeiH, FreiB. The iron chelator, desferrioxamine, reduces inflammation and atherosclerotic lesion development in experimental mice. Exp Biol Med (Maywood). 2010;235(5):633-641.

[97] WuD, HuQ, WangY, Jin M, TaoZ, WanJ. Identification of HMOX1 as a critical Ferroptosis-related gene in atherosclerosis. Front Cardiovas Med. 2022;9:833642.

[98] YouJ, OuyangS, XieZ, et al. The suppression of hyperlipid diet-induced ferroptosis of vascular smooth muscle cells protests against atherosclerosis independent of p53/SCL7A11/GPX4 axis. J Cell Physiol. 2023;238:1891-1908.

[99] BaiT, LiM, LiuY, QiaoZ, WangZ. Inhibition of ferroptosis alleviates atherosclerosis through attenuating lipid peroxidation and endothelial dysfunction in mouse aortic endothelial cell. Free Radic Biol Med. 2020;160:92-102.

[100] Gafter-GviliA, Schechter A, Rozen-ZviB. Iron deficiency anemia in chronic kidney disease. Acta Haematol. 2019;142(1):44-50.

[101] LiB, WangZ, HongJ, et al. Iron deficiency promotes aortic medial degeneration via destructing cytoskeleton of vascular smooth muscle cells. Clin Transl Med. 2021;11(1):e276.

[102] SawadaH, HaoH, NaitoY, et al. Aortic iron overload with oxidative stress and inflammation in human and murine abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol. 2015;35(6):1507-1514.

[103] HeX, XiongY, LiuY, LiY, ZhouH, Wu K. Ferrostatin-1 inhibits ferroptosis of vascular smooth muscle cells and alleviates abdominal aortic aneurysm formation through activating the SLC7A11/GPX4 axis. FASEB J. 2024;38(2):e23401.

[104] ChenY, YiX, HuoB, et al. BRD4770 functions as a novel ferroptosis inhibitor to protect against aortic dissection. Pharmacol Res. 2022;177:106122.

[105] LiN, YiX, HeY, et al. Targeting Ferroptosis as a novel approach to alleviate aortic dissection. Int J Biol Sci. 2022;18(10):4118-4134.

[106] SampilvanjilA, Karasawa T, YamadaN, et al. Cigarette smoke extract induces ferroptosis in vascular smooth muscle cells. Am J Physiol Heart Circ Physiol. 2020;318(3):H508-h518.

[107] JiQX, ZengFY, ZhouJ, et al. Ferroptotic stress facilitates smooth muscle cell dedifferentiation in arterial remodelling by disrupting mitochondrial homeostasis. Cell Death Differ. 2023;30(2):457-474.

[108] ZhangS, BeiY, HuangY, et al. Induction of ferroptosis promotes vascular smooth muscle cell phenotypic switching and aggravates neointimal hyperplasia in mice. Mol Med. 2022;28(1):121.

[109] MaWQ, SunXJ, ZhuY, LiuNF. Metformin attenuates hyperlipidaemia-associated vascular calcification through anti-ferroptotic effects. Free Radic Biol Med. 2021;165:229-242.

[110] ShaoS, LiuY, HongW, et al. Influence of FOSL1 inhibition on vascular calcification and ROS generation through Ferroptosis via P53-SLC7A11 Axis. Biomedicine. 2023;11(2):635.

[111] YeY, ChenA, LiL, et al. Repression of the antiporter SLC7A11/glutathione/glutathione peroxidase 4 axis drives ferroptosis of vascular smooth muscle cells to facilitate vascular calcification. Kidney Int. 2022;102(6):1259-1275.

[112] SongY, YangN, SiH, et al. Iron overload impairs renal function and is associated with vascular calcification in rat aorta. Biometals. 2022;35(6):1325-1339.

[113] ChenZ, SunX, LiX, LiuN. Oleoylethanolamide alleviates hyperlipidaemia-mediated vascular calcification via attenuating mitochondrial DNA stress triggered autophagy-dependent ferroptosis by activating PPARα. Biochem Pharmacol. 2023;208:115379.

[114] JinR, YangR, CuiC, et al. Ferroptosis due to cystathionine γ lyase/hydrogen sulfide downregulation under high hydrostatic pressure exacerbates VSMC dysfunction. Front Cell Dev Biol. 2022;10:829316.

[115] ZhangJ, XieSA, WangJ, et al. Echinatin maintains glutathione homeostasis in vascular smooth muscle cells to protect against matrix remodeling and arterial stiffening. Matrix Biol. 2023;119:1-18.

[116] WeldyCS, Luttrell IP, WhiteCC, et al. Glutathione (GSH) and the GSH synthesis gene Gclm modulate vascular reactivity in mice. Free Radic Biol Med. 2012;53(6):1264-1278.

[117] SmithTG, TalbotNP, PrivatC, et al. Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: two randomized controlled trials. JAMA. 2009;302(13):1444-1450.

[118] FriseMC, ChengHY, NickolAH, et al. Clinical iron deficiency disturbs normal human responses to hypoxia. J Clin Invest. 2016;126(6):2139-2150.

[119] Lakhal-LittletonS, Crosby A, FriseMC, et al. Intracellular iron deficiency in pulmonary arterial smooth muscle cells induces pulmonary arterial hypertension in mice. Proc Natl Acad Sci U S A. 2019;116(26):13122-13130.

[120] WongCM, Preston IR, HillNS, SuzukiYJ. Iron chelation inhibits the development of pulmonary vascular remodeling. Free Radic Biol Med. 2012;53(9):1738-1747.

[121] HuP, XuY, JiangY, et al. The mechanism of the imbalance between proliferation and ferroptosis in pulmonary artery smooth muscle cells based on the activation of SLC7A11. Eur J Pharmacol. 2022;928:175093.

[122] ZhaoY, WangB, ZhangJ, et al. ALDH2 (aldehyde dehydrogenase 2) protects against hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2019;39(11):2303-2319.

[123] SunDY, WuWB, WuJJ, et al. Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence. Nat Commun. 2024;15(1):1429.

[124] AhmedMS, IkramS, BibiN, Mir A. Hutchinson-Gilford progeria syndrome: a premature aging disease. Mol Neurobiol. 2018;55(5):4417-4427.

[125] ZhangH, XiongZM, CaoK. Mechanisms controlling the smooth muscle cell death in progeria via down-regulation of poly(ADP-ribose) polymerase 1. Proc Natl Acad Sci U S A. 2014;111(22):E2261-E2270.

[126] MelocheJ, Pflieger A, VaillancourtM, et al. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation. 2014;129(7):786-797.

[127] LvZC, LiF, WangL, et al. Impact of parthanatos on the increased risk of onset and mortality in male patients with pulmonary hypertension. Am J Men’s Health. 2021;15(3):15579883211029458.

[128] MelocheJ, Le Guen M, PotusF, et al. miR-223 reverses experimental pulmonary arterial hypertension. Am J Physiol Cell Physiol. 2015;309(6):C363-C372.

[129] RoanJN, HsuCH, FangSY, et al. ProT-α gene transfer attenuates cardiopulmonary remedying and mortality in a flow-induced pulmonary hypertension rat model. J Heart Lung Transplant. 2020;39(10):1126-1135.

[130] SoldaniC, Scovassi AI, CanosiU, BramucciE, Ardissino D, ArbustiniE. Multicolor fluorescence technique to detect apoptotic cells in advanced coronary atherosclerotic plaques. Eur J Histochem. 2005;49(1):47-52.

[131] PerrottaI, Brunelli E, SciangulaA, et al. iNOS induction and PARP-1 activation in human atherosclerotic lesions: an immunohistochemical and ultrastructural approach. Cardiovas Pathol. 2011;20(4):195-203.

[132] Oumouna-BenachourK, Hans CP, SuzukiY, et al. Poly(ADP-ribose) polymerase inhibition reduces atherosclerotic plaque size and promotes factors of plaque stability in apolipoprotein E-deficient mice: effects on macrophage recruitment, nuclear factor-kappaB nuclear translocation, and foam cell death. Circulation. 2007;115(18):2442-2450.

[133] ZerfaouiM, SuzukiY, NauraAS, Hans CP, NicholsC, BoularesAH. Nuclear translocation of p65 NF-kappaB is sufficient for VCAM-1, but not ICAM-1, expression in TNF-stimulated smooth muscle cells: differential requirement for PARP-1 expression and interaction. Cell Signal. 2008;20(1):186-194.

[134] HansCP, Zerfaoui M, NauraAS, CatlingA, Boulares AH. Differential effects of PARP inhibition on vascular cell survival and ACAT-1 expression favouring atherosclerotic plaque stability. Cardiovasc Res. 2008;78(3):429-439.

[135] Del ReDP, Amgalan D, LinkermannA, LiuQ, KitsisRN. Fundamental mechanisms of regulated cell death and implications for heart disease. Physiol Rev. 2019;99(4):1765-1817.

[136] LiP, WangY, LiuX, et al. Loss of PARP-1 attenuates diabetic arteriosclerotic calcification via Stat1/Runx2 axis. Cell Death Dis. 2020;11(1):22.

[137] LiangES, BaiWW, WangH, et al. PARP-1 (poly[ADP-ribose] polymerase 1) inhibition protects from Ang II (angiotensin II)-induced abdominal aortic aneurysm in mice. Hypertension. 2018;72(5):1189-1199.

[138] DentonD, KumarS. Autophagy-dependent cell death. Cell Death Differ. 2019;26(4):605-616.

[139] ZhengYH, TianC, MengY, et al. Osteopontin stimulates autophagy via integrin/CD44 and p38 MAPK signaling pathways in vascular smooth muscle cells. J Cell Physiol. 2012;227(1):127-135.

[140] RouerM, XuBH, XuanHJ, et al. Rapamycin limits the growth of established experimental abdominal aortic aneurysms. Eur J Vas Endovas Surg. 2014;47(5):493-500.

[141] ZhouB, LiW, ZhaoG, et al. Rapamycin prevents thoracic aortic aneurysm and dissection in mice. J Vasc Surg. 2019;69(3):921-932.e3.

[142] LiR, YiX, WeiX, et al. EZH2 inhibits autophagic cell death of aortic vascular smooth muscle cells to affect aortic dissection. Cell Death Dis. 2018;9(2):180.

[143] ChenTQ, HuN, HuoB, et al. EHMT2/G9a inhibits aortic smooth muscle cell death by suppressing autophagy activation. Int J Biol Sci. 2020;16(7):1252-1263.

[144] ClémentM, Chappell J, RaffortJ, et al. Vascular smooth muscle cell plasticity and autophagy in dissecting aortic aneurysms. Arterioscler Thromb Vasc Biol. 2019;39(6):1149-1159.

[145] RamadanA, SinghKK, QuanA, et al. Loss of vascular smooth muscle cell autophagy exacerbates angiotensin II-associated aortic remodeling. J Vasc Surg. 2018;68(3):859-871.

[146] BedouiS, HeroldMJ, StrasserA. Emerging connectivity of programmed cell death pathways and its physiological implications. Nat Rev Mol Cell Biol. 2020;21(11):678-695.

[147] WangY, Kanneganti TD. From pyroptosis, apoptosis and necroptosis to PANoptosis: a mechanistic compendium of programmed cell death pathways. Comput Struct Biotechnol J. 2021;19:4641-4657.

[148] LiK, WeiM, ZhangD, Zhai S, LiuH. PANoptosis in vascular smooth muscle cells regulated by TNF-α/IL-1β can be a new target for alleviating the progression of abdominal aortic aneurysm. Physiol Genomics. 2024;56(2):158-166.

[149] FritschM, Günther SD, SchwarzerR, et al. Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature. 2019;575(7784):683-687.

[150] SchneiderKS, Groß CJ, DreierRF, et al. The inflammasome drives GSDMD-independent secondary pyroptosis and IL-1 release in the absence of caspase-1 protease activity. Cell Rep. 2017;21(13):3846-3859.

[151] RogersC, Fernandes-Alnemri T, MayesL, AlnemriD, Cingolani G, AlnemriES. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat Commun. 2017;8:14128.

[152] WangY, GaoW, ShiX, et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017;547(7661):99-103.

[153] RogersC, ErkesDA, NardoneA, Aplin AE, Fernandes-AlnemriT, AlnemriES. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat Commun. 2019;10(1):1689.

[154] MiyashitaT, ReedJC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995;80(2):293-299.

[155] MiyashitaT, Harigai M, HanadaM, ReedJC. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res. 1994;54(12):3131-3135.

[156] JiangL, KonN, LiT, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520(7545):57-62.

[157] HeC, ZhuH, ZhangW, et al. 7-Ketocholesterol induces autophagy in vascular smooth muscle cells through Nox4 and Atg4B. Am J Pathol. 2013;183(2):626-637.

[158] BoyleJJ, BowyerDE, WeissbergPL, Bennett MR. Human blood-derived macrophages induce apoptosis in human plaque-derived vascular smooth muscle cells by Fas-ligand/Fas interactions. Arterioscler Thromb Vasc Biol. 2001;21(9):1402-1407.

[159] Silvestre-RoigC, Braster Q, WichapongK, et al. Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death. Nature. 2019;569(7755):236-240.

[160] Méndez-BarberoN, Gutiérrez-Muñoz C, Blanco-ColioLM. Cellular crosstalk between endothelial and smooth muscle cells in vascular wall remodeling. Int J Mol Sci. 2021;22(14):7284.

[161] ZhangL, XuQ. Stem/progenitor cells in vascular regeneration. Arterioscler Thromb Vasc Biol. 2014;34(6):1114-1119.

[162] XieY, FanY, XuQ. Vascular regeneration by stem/progenitor cells. Arterioscler Thromb Vasc Biol. 2016;36(5):e33-e40.

[163] ZhangJ, DingW, ZhaoM, et al. Mechanisms of efferocytosis in determining inflammation resolution: therapeutic potential and the association with cardiovascular disease. Br J Pharmacol. 2022;179(23):5151-5171.

[164] BerthelootD, LatzE, FranklinBS. Necroptosis, pyroptosis and apoptosis: an intricate game of cell death. Cell Mol Immunol. 2021;18(5):1106-1121.

[165] GrootaertMO, Schrijvers DM, HermansM, Van HoofVO, De Meyer GR, MartinetW. Caspase-3 deletion promotes necrosis in atherosclerotic plaques of ApoE knockout mice. Oxid Med Cell Longev. 2016;2016:3087469.

RIGHTS & PERMISSIONS

2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.