Signaling pathways and targeted therapy for myocardial infarction

Abstract

Although the treatment of myocardial infarction (MI) has improved considerably, it is still a worldwide disease with high morbidity and high mortality. Whilst there is still a long way to go for discovering ideal treatments, therapeutic strategies committed to cardioprotection and cardiac repair following cardiac ischemia are emerging. Evidence of pathological characteristics in MI illustrates cell signaling pathways that participate in the survival, proliferation, apoptosis, autophagy of cardiomyocytes, endothelial cells, fibroblasts, monocytes, and stem cells. These signaling pathways include the key players in inflammation response, e.g., NLRP3/caspase-1 and TLR4/MyD88/NF-κB; the crucial mediators in oxidative stress and apoptosis, for instance, Notch, Hippo/YAP, RhoA/ROCK, Nrf2/HO-1, and Sonic hedgehog; the controller of myocardial fibrosis such as TGF-β/SMADs and Wnt/β-catenin; and the main regulator of angiogenesis, PI3K/Akt, MAPK, JAK/STAT, Sonic hedgehog, etc. Since signaling pathways play an important role in administering the process of MI, aiming at targeting these aberrant signaling pathways and improving the pathological manifestations in MI is indispensable and promising. Hence, drug therapy, gene therapy, protein therapy, cell therapy, and exosome therapy have been emerging and are known as novel therapies. In this review, we summarize the therapeutic strategies for MI by regulating these associated pathways, which contribute to inhibiting cardiomyocytes death, attenuating inflammation, enhancing angiogenesis, etc. so as to repair and re-functionalize damaged hearts.

Fig. 1

Schematic diagram of the pathophysiology of different cell phenotypes and representative pathways involved in infarct hearts (created with BioRender.com). After myocardial infarction, various cell signaling pathways are activated. Oxidative stress and the death of tissue, particularly apoptotic and necrotic cardiomyocytes, trigger the inflammatory response. Immunocytes infiltrate the infarct area and release inflammatory factors. Meanwhile, cardiac fibroblasts transform into cardiac myofibroblasts and secrete extracellular matrix, and endothelial cells migrate, proliferate and form a network of blood vessels to promote the cardiac repair. However, pathological hypertrophy of the myocardium affected by inflammation, coupled with reactive fibrosis, would eventually lead to cardiac remodeling and heart failure. MAPK, mitogen-activated protein kinase; Hippo/YAP, Hippo/Yes-associated protein; RhoA/ROCK, Ras homolog family member A/Rho associated coiled-coil containing protein kinase; Nrf2/HO-1, nuclear factor erythroid derived 2-related factor 2/heme oxygenase-1; TLR4/MyD88/NF-κB Toll-like receptor 4/MyD88/nuclear factor-κB; NLRP3/caspase-1, the nucleotide-binding domain, leucine-rich-repeat family, pyrin-domain-containing 3/caspase-1; TGF-β/SMADs, transforming growth factor-β/SMADs; Wnt/β-catenin, Wingless/β-catenin; PI3K/Akt, phosphoinositide-3 kinase/protein kinase B; EndoMT. endothelial-to-mesenchymal transition

Fig. 2

a PI3K/Akt signaling pathway and targeted therapy in Myocardial infarction (MI). PI3K/Akt is involved in the regulation of cardiac remodeling, regeneration, and repair post-ischemia. This pathway responds to the stimulus, likewise growth factor/growth factor receptor signaling and so on. Phosphorylated PI3K and Akt activate the downstream molecules, VEGF, eNOS, while inhibiting mTOR(C1), GSK-3β, FOXO, respectively. GF, growth factor; GFR growth factor receptor, PI3K Phosphoinositide-3 kinase, Akt protein kinase B, PIP2 phosphatidylinositol 4,5-bisphosphate, PIP3 phosphatidylinositol 3,4,5-trisphosphate, PDK phosphoinositide dependent kinase, PH Pleckstrin homology, PTEN phosphatase and tensin homolog, VEGF vascular endothelial growth factor, eNOS endothelial nitric oxide synthase, mTORC1/2 mammalian target of rapamycin complex 1/2, GSK-3β glycogen synthase kinase 3β, FOXO forkhead box subfamily O, AZIN2-sv lncRNA-AZIN2 splice variant, S1P sphingosine-1-phosphate, Ezh2 enhancer of zeste homolog 2. b Notch signaling pathway and targeted therapy in MI. RBP-JК recombination signal-binding protein-JК, NICD notch intracellular domain, CSL CBF1/Rbpj (mammalian), Su(H) (Drosophila), and Lag-1 (Caenorhabditis elegans), CX Chuanxiong, CS Chishao VA velvet antler, YQHX Yiqihuoxue prescription, AGS astragaloside

Fig. 3

a NLRP3/caspase-1 signaling pathway and its correlated intervention after MI. NLRP3/caspase-1 inflammasome pathway mediated inflammation, pyroptosis, oxidative stress, fibrosis, cardiac remodeling following MI. When NLRP3 is activated by DAMPs and PAMPs, it binds to ASC adaptor molecule and aggregates with pro-caspase-1. Then the NLRP3 inflammasome converts pro-caspase-1 to caspase-1, which catalyzes the conversion of pro-IL-1β and pro-IL-18 to its mature product IL-1β and IL-18. ATP adenosine triphosphate, LPS lipopolysaccharide, PAMPs pathogen-associated molecular patterns, DAMPs Danger-associated molecular patterns, TLR4 toll-like receptor 4, NLRP3 nucleotide-binding domain, leucine-rich-repeat family, pyrin-domain-containing 3, ASC activating signal cointegrator, IL interleukin, NF-κB nuclear factor-κBn, OLT1177 Dapansutrile. b TLR4/MyD88/NF-κB signaling pathway and its correlated intervention after MI. TLR4/MyD88/NF-κB signaling pathway mediated inflammation, pyroptosis, apoptosis, fibrosis, ventricular arrhythmias and lipid metabolism after myocardial infarction. Cardiac injury generates endogenous signals that activate the TLR4/MyD88/NF-κB signaling pathway. The activation of the TLR signaling pathway originates from the cytoplasmic TIR domain that associates with a TIR domain-containing adaptor, MyD88. This signaling pathway activates NF-κB, a transcription factor, and subsequently induce the production of proinflammatory cytokines. TLR4 Toll-like receptor 4, TIRAP TIR (Toll/IL-1 receptor) domain-containing adapter protein, IRAK-4 IL-1 receptor-associated kinase-4, TRAF6 tumor necrosis factor receptor-associated factor 6, IKK IκB kinase, NF-κB Nuclear factor-κB, Lenti shRNA Lentivirus short hairpin RNA, TAK-242 resatorvid, RP-105 radioprotective 105

Fig. 4

a Nrf2/HO-1 signaling pathway and targeted therapy post MI. NRF2/HO-1 plays a crucial role in combating various oxidative stress responses and heart remodeling after MI. It exists in almost all kinds of cells in the body to maintain homeostasis and reduce oxidative stress. In addition, this pathway also plays an important role in stem cell therapy of MI and prognosis prediction of MI. KEAP1 kelch like ECH associated protein 1, NRF2 nuclear factor erythroid-derived 2-related factor 2, HO-1 heme oxygenase-1, ARE antioxidant responsive element, ROS reactive oxygen species. b RhoA/ROCK signaling pathway and targeted therapy post MI. RhoA switches back and forth between inactive GDP state and active GTP state, so as to play its biological role. ROCK is a downstream molecule of Rhoa. They all play a role in fibrosis, ventricular remodeling, and cardiac repair after myocardial infarction. Many drugs, including statins, can play their role in treating myocardial infarction by targeting the RhoA/ROCK pathway. RhoA Ras homolog family member A, ROCK Rho associated coiled-coil containing protein kinase, HIF-1α hypoxia inducible factor-1α, HMG-CoA hydroxymethylglutaryl-CoA, GAP GTPase-activating protein, GDI guanine dissociation inhibitor, GDP guanosine diphosphate, GTP guanosine triphosphate, GEF guanine nucleotide exchange factor

Fig. 5

a MAPK signaling pathway and targeted therapy post MI following MI. MAPKs are a class of highly conserved serine/threonine protein kinases in cells that transmit signals through a three-level cascade. There are four main branches of MAPK signaling pathway, namely the ERK, the c-JNK, the p38/MAPK and the ERK5. Hsp90 Heat shock protein 90, α1-AR Alpha1 adrenergic receptor, CXCR7 CXC chemokine receptor 7, Mst1 mammalian sterile 20-like kinase 1, EPO erythropoietin. b JAK/STAT signaling pathway and targeted therapy following MI. JAK/STAT regulates transmembrane receptor and nuclear communication through four steps: (1) Cytokines bind to receptors, leading to dimerization of receptor molecules, and JAKs are activated and phosphorylated; (2) STAT protein is recruited to the docking site formed by these phosphorylated tyrosine sites; (3) STATs are phosphorylated and activated, which enables them to dimerize; and (4) STAT–STAT dimer translocates to the nucleus and regulates gene expression. JAK Janus kinase, STAT signal transduction and activator of transcription, EGCG epigallocatechin-3-gallate, gp130 glycoprotein 130, VEGF vascular endothelial growth factor, Bcl-2 B-cell lymphoma-2, iNOS inductible nitric oxide synthase

Fig. 6

a TGF-β/SMADs signaling pathway and targeted therapy in MI. After TGF-β family binds to TGFβRII, TGFβRI is phosphorylated on specific serine and threonine residues, and finally forms a heterocomplex. The receptor complex reacts with the downstream effector molecule SMADs protein and eventually regulates the transcription of the target gene. RI receptors type I, RII receptors type II, TF transcriptional factor, R-Smad receptor-regulated Smad, Co-Smad common Smad, I-Smad inhibitory Smad, TMAO trimethylamine N-oxide, KLF5 Kruppel-like factor 5, Cytl1 cytokine-Like 1, ANO1 Anoctamin-1, CTRP9 C1q/tumor necrosis factor-related protein-9. b Wnt/β-catenin signaling pathway and targeted therapy in MI. Wnt signaling is considered as a basic growth regulation pathway. The binding of Wnt to the Frizzled receptor family and low-density lipoprotein receptor-related protein 5 (LRP5) or LRP6 co-receptors stimulates the canonical Wnt/β-catenin signaling pathway, thereby regulating the stability of β-catenin and context-related transcription. Wnt wingless, LRP LDL receptor-related protein, APC adenomatous polyposis coli, GSK-3β glycogen synthase kinase 3β, VEGF vascular endothelial growth factor, SMAD small mother against decapentaplegic, IL interleukin, DKK2 Dickkopf-related protein 2

Fig. 7

a Hippo/YAP signaling pathway and targeted therapy after MI. Canonical and noncanonical Hippo pathways are vital mechanisms of homeostasis, repair, and regeneration in the heart. In canonical Hippo/YAP, when the pathway turns “on”, the activated MST, SAV, LATS, and MOB leads phosphorylated YAP/TAZ detained in the cytoplasm or degraded, progressively. In contrast, the pathway turns “off” up-regulating the coaction of YAP/TAZ and other transcription factors. MST1/2 mammalian sterile 20-like kinases 1/2, SAV1 salvador family protein 1, LATS1/2 large tumor suppressors 1/2, MOB1A/1B Mps one binder kinase activator-like 1A/1B, YAP Yes-associated protein, TAZ PDZ-binding motif. b Sonic Hedgehog signaling pathway and its correlated intervention after MI. Shh Sonic Hedgehog, Ptc Patched, Smo smoothened, Gli glioma-associated oncogene homolog, TMP tetramethylpyrazine, AGS astragaloside

Fig. 8

Novel targeted therapeutic strategies and mechanisms in MI treatment (Created with BioRender.com). In terms of the signaling pathways, potential therapeutic strategies for MI that have been proposed to include drug, gene therapy, protein therapy, cell therapy, and exosome therapy. According to the pathological process of MI, the specific targeted mechanism of these therapies could be classified into four categories: (1) anti-inflammation, (2) anti-fibrosis, (3) cardioprotection and cardiac regeneration, and (4) pro-angiogenesis. Dot-labeled subtitles refer to the representative targeting drugs or bioactive molecules. ACEI angiotensin converting enzyme inhibitor, ARB angiotensin receptor antagonist, EPCs endothelial progenitor cells, lncRNA long non-coding RNA, miRNA microRNA, mTOR mammalian target of rapamycin, NAC N-acetylcysteine, NLRP3 nucleotide-binding domain, leucine-rich-repeat family, pyrin-domain-containing 3, PTEN phosphatase and tensin homolog, TGF-β1 transforming growth factor-β1, IL-1β interleukin-1β, TLR4 Toll-like receptor 4, NF-κB nuclear factor-κB, MSCs mesenchymal stem cells

Fig. 9

Cell signaling pathways participant in regulating pathological processes and phenotypes after MI (Created with BioRender.com). PI3K/Akt phosphoinositide-3 kinase/protein kinase B, TGF-β/SMADs transforming growth factor-β/SMADs, Wnt/β-catenin wingless/β-catenin, NLRP3/caspase-1 nucleotide-binding domain, leucine-rich-repeat family, pyrin-domain-containing 3/caspase-1, TLR4/MyD88/NF-κB toll-like receptor 4/MyD88/Nuclear factor-κB, Nrf2/HO-1 nuclear factor erythroid derived 2-related factor 2/heme oxygenase-1, MAPK mitogen-activated protein kinase, JAK/STAT Janus kinase/signal transducer and activator of transcription, Hippo/YAP Hippo/Yes-associated protein