# The Landscape of SERCA2 in Cardiovascular Diseases: Expression Regulation, Therapeutic Applications, and Emerging Roles **Authors:** Jianmin Wu, Mengting Liao, Tengkun Dai, Guiyan Liu, Jiayi Zhang, Yiling Zhu, Lin Xu, Juanjuan Zhao PMC · DOI: 10.3390/biom16020247 · Biomolecules · 2026-02-04 ## TL;DR This paper reviews the role of SERCA2 in cardiovascular diseases, focusing on how it regulates calcium and could be a target for new treatments. ## Contribution The paper systematically explores SERCA2's regulatory mechanisms and its potential as a therapeutic target in cardiovascular diseases. ## Key findings - SERCA2 dysfunction is linked to heart failure, cardiac hypertrophy, atherosclerosis, and diabetic cardiomyopathy. - SERCA2 regulation involves transcriptional control, post-translational modifications, and protein–protein interactions. - Abnormal SERCA2 function disrupts intracellular calcium homeostasis, contributing to cardiovascular disease progression. ## Abstract Driven by rapid socioeconomic progress and changing lifestyles, the global burden of cardiovascular diseases (CVDs) continues to escalate, with surging morbidity and mortality rates imposing a severe threat to public health. Clinical treatments are focused on the alleviation of treatments, highlighting the need for a deeper understanding of CVDs pathogenesis and the development of targeted therapies. Recent studies have identified imbalances in intracellular Ca2+ homeostasis as a key pathological mechanism in the progression of CVDs. Notably, sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2), a membrane protein encoded by the ATP2A2 gene and ranging from 97 to 115 kDa in molecular weight, plays a pivotal role in regulating intracellular Ca2+ levels. Extensive evidence links abnormal SERCA2 function to various CVDs, including heart failure, cardiac hypertrophy, atherosclerosis, and diabetic cardiomyopathy. This review systematically explores the regulatory mechanisms of SERCA2 expression and its functional regulation—including transcriptional regulation, post-translational modifications, and protein–protein interactions—and further investigates its pathological roles in cardiovascular diseases as well as its potential as a therapeutic target. By synthesizing current knowledge, this article aims to provide new insights for future basic research and establish a theoretical foundation for clinical applications. ## Linked entities - **Genes:** ATP2A2 (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2) [NCBI Gene 488] - **Proteins:** ATP2A2 (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2) - **Diseases:** heart failure (MONDO:0005252), atherosclerosis (MONDO:0005311) ## Full-text entities - **Genes:** BIN1 (bridging integrator 1) [NCBI Gene 274] {aka AMPH2, AMPHL, CNM2, SH3P9}, Pde5a (phosphodiesterase 5A, cGMP-specific) [NCBI Gene 242202] {aka Cgbpde, Cn5n, PDE5a2, Pde5, Pde5a1}, Slc8a1 (solute carrier family 8 (sodium/calcium exchanger), member 1) [NCBI Gene 20541] {aka D930008O12Rik, Ncx1}, Pln (phospholamban) [NCBI Gene 64672] {aka Plm}, Atp2a2 (ATPase, Ca++ transporting, cardiac muscle, slow twitch 2) [NCBI Gene 11938] {aka 9530097L16Rik, D5Wsu150e, SERCA2, SERCA2B, Serca2a, mKIAA4195}, Zfas1 (zinc finger, NFX1-type containing 1, antisense RNA 1) [NCBI Gene 68949] {aka 1500012F01Rik, Zfos1}, Nfatc3 (nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 3) [NCBI Gene 18021] {aka D8Ertd281e, NFAT4, NFATx}, Hsp90b1 (heat shock protein 90, beta (Grp94), member 1) [NCBI Gene 22027] {aka ERp99, GRP94, TA-3, Targ2, Tra-1, Tra1}, Akr1b1 (aldo-keto reductase family 1 member B) [NCBI Gene 11677] {aka ALR2, AR, Ahr-1, Ahr1, Akr1b3, Aldor1}, Ppp1ca (protein phosphatase 1 catalytic subunit alpha) [NCBI Gene 24668] {aka PP1alpha}, Ttc21b (tetratricopeptide repeat domain 21B) [NCBI Gene 73668] {aka 2410066K11Rik, Thm1, aln, mKIAA1992}, Gapdh (glyceraldehyde-3-phosphate dehydrogenase) [NCBI Gene 14433] {aka Gapd}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, Atp2a1 (ATPase, Ca++ transporting, cardiac muscle, fast twitch 1) [NCBI Gene 11937] {aka SERCA1}, Mir221 (microRNA 221) [NCBI Gene 100314163] {aka rno-mir-221}, Gata4 (GATA binding protein 4) [NCBI Gene 14463] {aka Gata-4}, OGT (O-linked N-acetylglucosamine (GlcNAc) transferase) [NCBI Gene 8473] {aka HINCUT-1, HRNT1, MRX106, O-GLCNAC, OGT1, XLID106}, Nexn (nexilin) [NCBI Gene 68810] {aka 1110046H09Rik, NELIN}, Ldlr (low density lipoprotein receptor) [NCBI Gene 16835] {aka Hlb301}, Sds (serine dehydratase) [NCBI Gene 231691] {aka 4432411H13Rik, SDH}, Ube2i (ubiquitin-conjugating enzyme E2I) [NCBI Gene 22196] {aka 5830467E05Rik, UBC9, Ubce2i, Ubce9}, Speg (SPEG complex locus) [NCBI Gene 11790] {aka APEG-1, Apeg1, BPEG, D1Bwg1450e, SPEGalpha, SPEGbeta}, Rhoa (ras homolog family member A) [NCBI Gene 11848] {aka Arha, Arha1, Arha2}, Atp2a3 (ATPase, Ca++ transporting, ubiquitous) [NCBI Gene 53313] {aka SERCA3b, Serca3}, Sln (sarcolipin) [NCBI Gene 66402] {aka 2310045A07Rik}, Ryr2 (ryanodine receptor 2, cardiac) [NCBI Gene 20191] {aka 9330127I20Rik, RYR-2}, Ryr1 (ryanodine receptor 1, skeletal muscle) [NCBI Gene 20190] {aka RYR-1, Ryr, skrr}, Stk16 (serine/threonine kinase 16) [NCBI Gene 20872] {aka EDPK, Krct, MPSK, PKL12, TSF-1}, Hax1 (HCLS1 associated X-1) [NCBI Gene 23897] {aka HAX-1, HSP1BP-1, Hs1bp1, SIG-111, Silg111, mHAX-1s}, ATP2A2 (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2) [NCBI Gene 488] {aka ATP2B, DAR, DD, RHABDO2, SERCA2}, Nox4 (NADPH oxidase 4) [NCBI Gene 50490], Bfar (bifunctional apoptosis regulator) [NCBI Gene 67118] {aka 3010001A07Rik, 3110001I22Rik, Bar, Rnf47}, Casq1 (calsequestrin 1) [NCBI Gene 12372] {aka CSQ, CSQ-1, CSQ1, sCSQ}, Pparg (peroxisome proliferator activated receptor gamma) [NCBI Gene 19016] {aka Nr1c3, PPAR-gamma, PPAR-gamma2, PPARgamma, PPARgamma2}, Dnah8 (dynein, axonemal, heavy chain 8) [NCBI Gene 13417] {aka ATPase, Dnahc8, Hst6.7b, P1-Loop}, Txn1 (thioredoxin 1) [NCBI Gene 22166] {aka ADF, Trx1, Txn}, Ep300 (E1A binding protein p300) [NCBI Gene 328572] {aka A430090G16, A730011L11, KAT3B, p300, p300 HAT}, Mef2c (myocyte enhancer factor 2C) [NCBI Gene 17260] {aka 5430401D19Rik, 9930028G15Rik, Mef2}, Pln (phospholamban) [NCBI Gene 18821] {aka Plb}, Mir25 (microRNA 25) [NCBI Gene 723926] {aka Mirn25, mir-25, mmu-mir-25}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, Ern1 (endoplasmic reticulum to nucleus signalling 1) [NCBI Gene 78943] {aka 9030414B18Rik, Ire1a, Ire1alpha, Ire1p}, Cdk2 (cyclin dependent kinase 2) [NCBI Gene 12566] {aka A630093N05Rik}, Sumo1 (small ubiquitin-like modifier 1) [NCBI Gene 22218] {aka GMP1, PIC1, SENTRIN, SMT3, SMT3H3, SMTP3}, Agtrap (angiotensin II, type I receptor-associated protein) [NCBI Gene 11610] {aka 3300002E14Rik, AT1R, Atrap, D4Wsu124e}, Mrln (myoregulin) [NCBI Gene 69563] {aka 2310015B20Rik, Linc-RAM, Mln}, Gsr (glutathione reductase) [NCBI Gene 14782] {aka D8Ertd238e, Gr-1, Gr1}, Camk2g (calcium/calmodulin-dependent protein kinase II gamma) [NCBI Gene 12325] {aka Camkg}, Eln (elastin) [NCBI Gene 13717] {aka E030024M20Rik}, Sp1 (trans-acting transcription factor 1) [NCBI Gene 20683] {aka 1110003E12Rik, Sp1-1}, Hrc (histidine rich calcium binding protein) [NCBI Gene 15464], S100a1 (S100 calcium binding protein A1) [NCBI Gene 20193] {aka S100, S100a}, Calm2 (calmodulin 2) [NCBI Gene 12314] {aka 1500001E21Rik, Cam2, CamC}, Cdk1 (cyclin dependent kinase 1) [NCBI Gene 12534] {aka Cdc2, Cdc2a, p34}, Agt (angiotensinogen) [NCBI Gene 11606] {aka AngI, AngII, Aogen, Serpina8}, Atp2a2 (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2) [NCBI Gene 29693] {aka Serca2, SercaII}, Tfb2m (transcription factor B2, mitochondrial) [NCBI Gene 15278] {aka Hkp1, mTFB2M, mtTFB2}, Mir146 (microRNA 146) [NCBI Gene 387164] {aka Mirn146, miR-146a, mmu-mir-146}, Tfam (transcription factor A, mitochondrial) [NCBI Gene 21780] {aka Hmgts, mtTFA, tsHMG}, Mir29c (microRNA 29c) [NCBI Gene 387224] {aka Mirn29c, mir-29c, mmu-mir-29c} - **Diseases:** death (MESH:D003643), diabetic complications (MESH:D048909), hypothyroid (MESH:D007037), hyperglycemic (MESH:D006944), hypertension (MESH:D006973), DC (MESH:D058065), Pulmonary Arterial Hypertension (MESH:D000081029), Atherosclerosis (MESH:D050197), MIRI (MESH:D015427), cardiac function abnormalities (MESH:D000014), toxicity (MESH:D064420), vascular endothelial injury (MESH:D057772), bone injury (MESH:D001847), insulin resistance (MESH:D007333), cardiac diastolic interval (MESH:D006337), DCM (MESH:D002311), CVD (MESH:D002318), myocardial infarct (MESH:D009203), cardiopulmonary vascular remodeling disorder (MESH:D066253), Myocardial Hypertrophy (MESH:D006984), ischemic heart disease (MESH:D017202), hypertrophic (MESH:D002312), cardiac hypertrophy (MESH:D006332), right ventricular hypertrophy and failure (MESH:D017380), cardiac autonomic neuropathy (MESH:D006331), coronary artery disease (MESH:D003324), T2D (MESH:D003924), HF (MESH:D006333), myocardial systole (MESH:D000092244), cardiac systolic and diastolic dysfunction (MESH:D054144), PH (MESH:D006976), necrotic (MESH:D009336), PASMC (MESH:D018235), neointimal hyperplasia (MESH:D006965), mitochondrial dysfunction (MESH:D028361), coronary heart disease (MESH:D003327), inflammation (MESH:D007249), injury to (MESH:D014947), hyperglycemia (MESH:D006943), calcium overload (MESH:D019190), Myocardial fibrosis (MESH:D005355), SKI (MESH:D056304), aortic aneurysm (MESH:D001014), DM2 (MESH:D009223), diastolic insufficiency (MESH:D000309), DM (MESH:D003920), ischemic (MESH:D002545), cardiomyopathy (MESH:D009202), acute heart failure syndrome (MESH:D058186), stroke (MESH:D020521), obesity (MESH:D009765), hypoxia (MESH:D000860), iron (MESH:D000090463), metabolic diseases (MESH:D008659), ischemia (MESH:D007511), inability (MESH:C564980) - **Chemicals:** Sildenafil (MESH:D000068677), disulfide (MESH:D004220), levocarnitine (MESH:D002331), superoxide (MESH:D013481), 15N (-), NO (MESH:D009614), lignans (MESH:D017705), sulfhydryl (MESH:D013438), micropeptides (MESH:C000722334), NADP (MESH:D009249), lipid (MESH:D008055), cysteine (MESH:D003545), Digoxin (MESH:D004077), ATP (MESH:D000255), fructose (MESH:D005632), HNO (MESH:C039900), CDN1163 (MESH:C000609635), peroxynitrite (MESH:D030421), GSH (MESH:D005978), glucose (MESH:D005947), Calcium (MESH:D002118), ROS (MESH:D017382), SR (MESH:D013324), NAD+ (MESH:D009243), Istaroxime (MESH:C468128), RNS (MESH:D011886), simvastatin (MESH:D019821), E2-P (MESH:C029085), cGMP (MESH:D006152), ADP (MESH:D000244), polyol (MESH:C024617), E2 (MESH:D004958), nitrotyrosine (MESH:C002744), streptozotocin (MESH:D013311), Sorbitol (MESH:D013012), oligonucleotides (MESH:D009841) - **Species:** Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116], Oryctolagus cuniculus (domestic rabbit, species) [taxon 9986], Mus musculus (house mouse, species) [taxon 10090] - **Mutations:** C674S, S674, S68A, Cys674, Serine/threonine, C674, lysine residues 480 - **Cell lines:** PASMC — Homo sapiens (Human), Finite cell line (CVCL_6775) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12938818/full.md ## Figures 4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12938818/full.md ## References 155 references — full list in the complete paper: https://tomesphere.com/paper/PMC12938818/full.md --- Source: https://tomesphere.com/paper/PMC12938818