# An Overview of the Molecular Mechanisms Associated with Myocardial Ischemic Injury: State of the Art and Translational Perspectives **Authors:** Leonardo Schirone, Maurizio Forte, Luca D’Ambrosio, Valentina Valenti, Daniele Vecchio, Sonia Schiavon, Giulia Spinosa, Gianmarco Sarto, Vincenzo Petrozza, Giacomo Frati, Sebastiano Sciarretta PMC · DOI: 10.3390/cells11071165 · 2022-03-30 ## TL;DR This paper reviews the molecular causes of heart damage from heart attacks and explores new ways to protect the heart and reduce long-term damage. ## Contribution The paper provides a comprehensive review of recent advances in understanding molecular mechanisms of myocardial ischemic injury and potential therapies. ## Key findings - Molecular mechanisms like ROS overproduction and mitochondrial dysfunction contribute to myocardial ischemic injury. - New therapeutic interventions aim to boost cardioprotection and reduce cardiac remodeling. - Metabolic alterations and autophagy deregulation are key factors in post-ischemic cardiac remodeling. ## Abstract Cardiovascular disease is the leading cause of death in western countries. Among cardiovascular diseases, myocardial infarction represents a life-threatening condition predisposing to the development of heart failure. In recent decades, much effort has been invested in studying the molecular mechanisms underlying the development and progression of ischemia/reperfusion (I/R) injury and post-ischemic cardiac remodeling. These mechanisms include metabolic alterations, ROS overproduction, inflammation, autophagy deregulation and mitochondrial dysfunction. This review article discusses the most recent evidence regarding the molecular basis of myocardial ischemic injury and the new potential therapeutic interventions for boosting cardioprotection and attenuating cardiac remodeling. ## Linked entities - **Diseases:** myocardial infarction (MONDO:0005068), heart failure (MONDO:0005252) ## Full-text entities - **Genes:** BNIP3 (BCL2 interacting protein 3) [NCBI Gene 664] {aka HABON, NIP3}, Kit (Kit proto-oncogene receptor tyrosine kinase) [NCBI Gene 16590] {aka Bs, CD117, Fdc, Gsfsco1, Gsfsco5, Gsfsow3}, SLC2A4 (solute carrier family 2 member 4) [NCBI Gene 6517] {aka GLUT4}, MST1 (macrophage stimulating 1) [NCBI Gene 4485] {aka D3F15S2, DNF15S2, HGFL, MSP, NF15S2}, Nos2 (nitric oxide synthase 2) [NCBI Gene 24599] {aka Nos2a, iNos}, GPX4 (glutathione peroxidase 4) [NCBI Gene 2879] {aka GPx-4, GSHPx-4, MCSP, PHGPx, SMDS, snGPx}, Tlx2 (T cell leukemia, homeobox 2) [NCBI Gene 21909] {aka Enx, Hox11L.1, Hox11l1, NCX, Ncx1, Tlx1l1}, Rheb (Ras homolog enriched in brain) [NCBI Gene 19744] {aka Rheb1}, DRD4 (dopamine receptor D4) [NCBI Gene 1815] {aka D4DR}, Sod2 (superoxide dismutase 2) [NCBI Gene 24787] {aka MnSOD}, PPARA (peroxisome proliferator activated receptor alpha) [NCBI Gene 5465] {aka NR1C1, PPAR, PPAR-alpha, PPARalpha, hPPAR}, Bcl2l1 (BCL2-like 1) [NCBI Gene 12048] {aka Bcl(X)L, Bcl-XL, Bcl2l, BclX, bcl-x, bcl2-L-1}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, Tnfrsf1a (tumor necrosis factor receptor superfamily, member 1a) [NCBI Gene 21937] {aka CD120a, FPF, TNF-R, TNF-R-I, TNF-R1, TNF-R55}, CD34 (CD34 molecule) [NCBI Gene 947], GSK3B (glycogen synthase kinase 3 beta) [NCBI Gene 2932], Opa1 (OPA1, mitochondrial dynamin like GTPase) [NCBI Gene 74143] {aka 1200011N24Rik, lilr3, mKIAA0567}, Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 25125], Nfe2l2 (nuclear factor, erythroid derived 2, like 2) [NCBI Gene 18024] {aka Nrf2}, SLC5A2 (solute carrier family 5 member 2) [NCBI Gene 6524] {aka SGLT2}, Ogt (O-linked N-acetylglucosamine (GlcNAc) transferase) [NCBI Gene 26295], MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, Hk2 (hexokinase 2) [NCBI Gene 25059], PYCARD (PYD and CARD domain containing) [NCBI Gene 29108] {aka ASC, CARD5, TMS, TMS-1, TMS1}, SLC9A1 (solute carrier family 9 member A1) [NCBI Gene 6548] {aka APNH, LIKNS, NHE-1, NHE1, PPP1R143}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, Becn1 (beclin 1, autophagy related) [NCBI Gene 56208] {aka Atg6}, GSDMD (gasdermin D) [NCBI Gene 79792] {aka DF5L, DFNA5L, FKSG10, GSDMDC1}, Akr1b1 (aldo-keto reductase family 1 member B1) [NCBI Gene 24192] {aka ALDRED, ALR-P-I, Akr1b3, Akr1b4, Aldr1, Alr}, Gsk3b (glycogen synthase kinase 3 beta) [NCBI Gene 84027], Mfn2 (mitofusin 2) [NCBI Gene 170731] {aka D630023P19Rik, Fzo}, Ppp1r12a (protein phosphatase 1, regulatory subunit 12A) [NCBI Gene 17931] {aka 1200015F06Rik, 5730577I22Rik, D10Ertd625e, Mypt1}, GCG (glucagon) [NCBI Gene 2641] {aka GLP-1, GLP1, GLP2, GRPP}, Ppif (peptidylprolyl isomerase F (cyclophilin F)) [NCBI Gene 105675] {aka CyP-D, CyP-F, CypD, PPIase}, PRKCD (protein kinase C delta) [NCBI Gene 5580] {aka ALPS3, CVID9, MAY1, PKCD, nPKC-delta}, Fis1 (fission, mitochondrial 1) [NCBI Gene 66437] {aka 2010003O14Rik, Ttc11}, Vegfa (vascular endothelial growth factor A) [NCBI Gene 83785] {aka VEGF-A, VEGF111, VEGF164, VPF, Vegf}, Map3k14 (mitogen-activated protein kinase kinase kinase 14) [NCBI Gene 53859] {aka Nik, aly}, Hmgb1 (high mobility group box 1) [NCBI Gene 15289] {aka HMG-1, Hmg1, SBP-1, p30}, 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}, Akt1 (AKT serine/threonine kinase 1) [NCBI Gene 24185] {aka Akt}, Rubcn (RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein) [NCBI Gene 100502698] {aka 1700021K19Rik, 5330403K09, Rubicon, mKIAA0226}, Ripk3 (receptor-interacting serine-threonine kinase 3) [NCBI Gene 56532] {aka 2610528K09Rik, Rip3}, Mir144 (microRNA 144) [NCBI Gene 387162] {aka Mirn144, mir-144, mmu-mir-144}, Foxo3 (forkhead box O3) [NCBI Gene 56484] {aka 1110048B16Rik, 2010203A17Rik, FKHRL1, Fkhr2, Foxo3a}, OPA1 (OPA1 mitochondrial dynamin like GTPase) [NCBI Gene 4976] {aka BERHS, MGM1, MTDPS14, MTDPS14A, MTDPS14B, NPG}, Il1rn (interleukin 1 receptor antagonist) [NCBI Gene 16181] {aka F630041P17Rik, IL-1ra}, Timp3 (tissue inhibitor of metalloproteinase 3) [NCBI Gene 21859] {aka Timp-3}, Adam17 (a disintegrin and metallopeptidase domain 17) [NCBI Gene 11491] {aka CD156b, Tace}, Cdh2 (cadherin 2) [NCBI Gene 12558] {aka CDHN, N-CAD, Ncad}, TXNIP (thioredoxin interacting protein) [NCBI Gene 10628] {aka ARRDC6, EST01027, HHCPA78, THIF, VDUP1}, PRKAB1 (protein kinase AMP-activated non-catalytic subunit beta 1) [NCBI Gene 5564] {aka AMPK, HAMPKb}, Nlrp3 (NLR family, pyrin domain containing 3) [NCBI Gene 287362] {aka Cias1}, Slc9a1 (solute carrier family 9 (sodium/hydrogen exchanger), member 1) [NCBI Gene 20544] {aka Apnh, Mir5122, Nhe1, mir-5122, swe}, PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 5295] {aka AGM7, GRB1, IMD36, p85, p85-ALPHA, p85alpha}, Bak1 (BCL2-antagonist/killer 1) [NCBI Gene 12018] {aka Bak, N-BAK1, N-Bak}, Bax (BCL2-associated X protein) [NCBI Gene 12028], Mmp3 (matrix metallopeptidase 3) [NCBI Gene 17392] {aka EMS-2, MMP-3, SL-1, SLN-1, SLN1, STR-1}, Ctnnb1 (catenin beta 1) [NCBI Gene 12387] {aka Bfc, Catnb, Mesc}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53} - **Diseases:** Coronary artery spasm (MESH:D003329), PVC (MESH:D018880), Diabetic (MESH:D003920), cardiac rupture (MESH:D006341), mPTP (MESH:D008579), ventricular hypertrophy and dilation (MESH:D024741), hematological diseases (MESH:D006402), fibrosis (MESH:D005355), myocardial (MESH:D009202), necrosis (MESH:D009336), Mitochondrial swelling (MESH:D028361), type I diabetes (MESH:D003922), tumors (MESH:D009369), -ischemic cardiac remodeling (MESH:D020257), aortic stenosis (MESH:D001024), swelling (MESH:D004487), left anterior descending artery (LAD) occlusion (MESH:D001157), ventricular dilation (MESH:C566255), metabolic derangements (MESH:D008659), stenosis (MESH:D003251), mitochondrial fragmentation (MESH:D012892), Microvascular dysfunction (MESH:D017566), I/R damage (MESH:D015427), /R. (MESH:C580424), ischemic myocardial contracture (MESH:D054061), thrombotic (MESH:D013927), heart failure (MESH:D006333), arrhythmia (MESH:D001145), insulin-resistant (MESH:D007333), type II diabetes (MESH:D003924), atherosclerosis (MESH:D050197), apoptosis (MESH:D065703), heart rigor contracture (MESH:D003286), Inflammation (MESH:D007249), IPC (MESH:D002545), CVDs (MESH:D002318), atrial fibrillation (MESH:D001281), Cell Death (MESH:D003643), defect (MESH:D000013), cardiac hypertrophy (MESH:D006332), coronary occlusion (MESH:D054059), phenotype (MESH:C537393), injury (MESH:D014947), C-I (MESH:C537475), atherosclerotic plaques (MESH:D058226), ASSAIL-MI (MESH:D009203), myocardial remodeling (MESH:D064752), heart infarction (MESH:D007238), arterial hypertension (MESH:D000081029), vascular sub-occlusion (MESH:D008641), cardiac aging and (MESH:D006331), anterior (MESH:D020759), hyperlipidemia (MESH:D006949), ST-segment elevation myocardial infarction (MESH:D000072657), Acute Myocardial Ischemia (MESH:D015472), hyperglycemia (MESH:D006943), Vascular remodeling (MESH:D066253), mitochondria (MESH:C564971), ischemia (MESH:D007511), anemia (MESH:D000740) - **Species:** Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606], Oryctolagus cuniculus (domestic rabbit, species) [taxon 9986], Mus musculus (house mouse, species) [taxon 10090] - **Cell lines:** H9c2 — Rattus norvegicus (Rat), Spontaneously immortalized cell line (CVCL_0286) ## Figures 7 figures with captions in the complete paper: https://tomesphere.com/paper/PMC8998015/full.md --- Source: https://tomesphere.com/paper/PMC8998015