Potential of natural drug modulation of endoplasmic reticulum stress in the treatment of myocardial injury

Abstract

Myocardial injury (MI) is a common occurrence in clinical practice caused by various factors such as ischemia, hypoxia, infection, metabolic abnormalities, and inflammation. Such damages are characterized by a reduction in myocardial function and cardiomyocyte death that can result in dangerous outcomes such as cardiac failure and arrhythmias. An endoplasmic reticulum stress (ERS)-induced unfolded protein response (UPR) is triggered by several stressors, and its intricate signaling networks are instrumental in both cell survival and death. Cardiac damage frequently triggers ERS in response to different types of injuries and stress. High levels of ERS can exacerbate myocardial damage by inducing necrosis and apoptosis. To target ERS in MI prevention and treatment, current medical research is focused on identifying effective therapy approaches. Traditional Chinese medicine (TCM) is frequently used because of its vast range of applications and low risk of adverse effects. Various studies have demonstrated that active components of Chinese medicines, including polyphenols, saponins, and alkaloids, can reduce myocardial cell death, inflammation, and modify the ERS pathway, thus preventing and mitigating cardiac injury. Thus, this paper aims to provide a new direction and scientific basis for targeting ERS in MI prevention and treatment. We specifically summarize recent research progress on the regulation mechanism of ERS in MI by active ingredients of TCM.

Keywords: Cardiovascular disease; Endoplasmic reticulum stress; Myocardial injury; Natural products; Unfolded protein response.

Graphical abstract

Fig. 1

Endoplasmic reticulum stress (ERS) activates adaptive signaling pathways. ER: endoplasmic reticulum; GRP78: glucose regulated protein78; IRE1: inositol-requiring enzyme 1; PERK: protein kinase RNA (PKR)-like ER kinase; ATF: activating transcription factor; XBP1: X-box-binding protein 1; ROS: reactive oxygen species; Nrf2: nuclear factor erythroid-2-related factor 2; eIF2α: eukaryotic translation initiation factor 2α; S1P: site 1 protease; S2P: site 2 protease; ATF6: activating transcription factor 6; ERAD: ER-associated degradation.

Fig. 2

Endoplasmic reticulum stress (ERS) activates pro-apoptotic signaling pathways. ER: endoplasmic reticulum; GRP78: glucose regulated protein78; IRE1: inositol-requiring enzyme 1; PERK: protein kinase RNA (PKR)-like ER kinase; ATF: activating transcription factor; eIF2α: eukaryotic translation initiation factor 2α; ATF4: activating transcription factor 4; ATF6: activating transcription factor 6; TRAF2: tumor necrosis factor receptor-associated factor 2; ASK1: apoptotic signaling kinase-1; JNK: c-Jun N-terminal kinase; S1P: site 1 protease; S2P: site 2 protease; IP3R1: inositol 1,4,5-trisphosphate receptor type 1; CaMKII: Ca²⁺/calmodulin-dependent protein kinase II; FAS: Fas cell surface death receptor; CHOP: C/EBP homologous protein; Bcl-2: BCL2 apoptosis regulator.

Fig. 3

Endoplasmic reticulum stress (ERS)-induced unfolded protein responses (UPRs) are associated with various signaling pathways in myocardial injury (MI). NADPH: nicotinamide adenine dinucleotide phosphate oxidase; ER: endoplasmic reticulum; ROS: reactive oxygen species; TXNIP: thioredoxin interacting protein; NLRP3: NLR family fyrin domain containing 3; IL-1β: interleukin 1beta; IRE1: inositol-requiring enzyme 1; TRAF2: tumor necrosis factor receptor-associated factor 2; IKK: inhibitor of kappa B kinase; NF-κB: nuclear factor kappa-B; IκB: inhibitor of NF-κB; PERK: protein kinase RNA (PKR)-like ER kinase; eIF2α: eukaryotic translation initiation factor 2α; ATF4: activating transcription factor 4; CHOP: CCAAT/enhancer-binding protein homologous protein; Bcl-2: BCL2 apoptosis regulator; ATF6: activating transcription factor 6.

Fig. 4

Molecular structure of natural products targeting endoplasmic reticulum stress (ERS) for treatment of myocardial injury (MI). APG: apigenin-7-O-β-d-(-6″-p-coumaroyl)-glucopyranoside.

Fig. 5

Natural products target endoplasmic reticulum stress (ERS) mediated myocardial injury (MI) in ischemia/reperfusion (I/R) injury. SIRT1: silencing information regulator 1; Nrf2: nuclear factor erythroid-2-related factor 2; HO-1: heme oxygenase 1; TRAF2: tumor necrosis factor receptor-associated factor 2; ASK1: apoptotic signaling kinase-1; JNK: c-Jun N-terminal kinase; Bcl-2: BCL2 apoptosis regulator; IRE1: inositol-requiring enzyme 1; XBP1: X-box-binding protein 1; TXNIP: thioredoxin interacting protein; ROS: reactive oxygen species; SOD: superoxide dismutase; CAT: catalase; GSH: glutathione; NLRP3: NLR family fyrin domain containing 3; TMBIM6: transmembrane BAX inhibitor-1 motif-containing 6; PERK: protein kinase RNA (PKR)-like endoplasmic reticulum (ER) kinase; AMPK: 5′ adenosine monophosphate-activated protein kinase; eIF2α: eukaryotic translation initiation factor 2α; ATF: activating transcription factor; HSP30: heat shock proteins30; RyR2: ryanodine receptor 2; CaMKII: Ca²⁺/calmodulin-dependent protein kinase II; CHOP: CCAAT/enhancer-binding protein homologous protein; p38: p38 mitogen-activated protein (MAP) kinase.

Fig. 6

Natural products target endoplasmic reticulum stress (ERS) mediated myocardial injury (MI) in heart failure, diabetic cardiomyopathy (DCM) and hypertensive. GRP78: glucose rregulated protein78; IRE1: inositol-requiring enzyme 1; PERK: protein kinase RNA (PKR)-like endoplasmic reticulum (ER) kinase; ATF6: activating transcription factor 6; ATF4: activating transcription factor 4; CHOP: CCAAT/enhancer-binding protein homologous protein; eNOS: endothelial-type nitricoxide synthase; NO: nitric oxide; CNPY2: cardiomyocyte-specific protein canopy homolog 2; NOX2: (nicotinamide adenine dinucleotide phosphate oxidase) NADPH oxidase 2; NOX4: NADPH oxidase 4; ROS: reactive oxygen species; COX2: cyclooxygenase-2; SIRT1: silencing information regulator 1; GRP78: glucose regulated protein78; JNK: c-Jun N-terminal kinase; AMPK: 5′ adenosine monophosphate-activated protein kinase; eIF2α: eukaryotic translation initiation factor 2α; MAPKs: mitogen-activated protein kinases; Bcl-2: BCL2 apoptosis regulator; AGEs: advanced glycosylation end products; TXNIP: thioredoxin interacting protein; NLRP3: NLR family fyrin domain containing 3; TNF-α: tumor necrosis factor-α; IL-1β: interleukin 1beta; IL-6: interleukin-6; ATF3: activating transcription factor 3.

Fig. 7

Natural products target endoplasmic reticulum stress (ERS) mediated myocardial injury (MI) in atherosclerosis, heat stress, alcoholic cardiomyopathy and weightlessness. GRP78: glucose regulated protein78; IRE1: inositol-requiring enzyme 1; PERK:protein kinase RNA (PKR)-like ER kinase; ATF6: activating transcription factor 6; AMPK: 5′ adenosine monophosphate-activated protein kinase; eIF2α: eukaryotic translation initiation factor 2α; ATF4: activating transcription factor 4; PPAR δ: peroxisome proliferator activated receptor gamma; NO: nitric oxide; CHOP: CCAAT/enhancer-binding protein homologous protein; NOX2: nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase 2; ROS: reactive oxygen species; TNF-α, tumor necrosis factor-α; MCP1: monocyte chemoattractant protein-1; IL-8: interleukin 8; LC3II: microtubule associated protein 1 light chain 3 beta; Mcl-1: MCL1 apoptosis regulator, BCL2 family member; CaMKII: Ca²⁺/calmodulin-dependent protein kinase II; HDAC4: histone deacetylase 4; Bcl-2: BCL2 apoptosis regulator.