ReviewEndoplasmic reticulum stress and focused drug discovery in cardiovascular disease
Section snippets
Introduction of endoplasmic reticulum stress
Endoplasmic reticulum (ER) is a multifunctional organelle that secretes proteins and transmembrane proteins for synthesis, folding, maturation and post-translation modification. In order for proteins to fold properly, a balance must be established between the ER protein load and the folding capacity. However, the increase of the physiological and pathological damage, including changes in intracellular calcium, genetic or environmental damage, oxidative stress, nutrient deprivation and
Relationship between endoplasmic reticulum stress and cardiovascular diseases
Cardiovascular disease is one of the leading causes of death worldwide. In recent years, there has been increasing evidence that ERS can cause ischemic heart disease, atherosclerosis, cardiac hypertrophy, hypertension, cardiomyopathy, heart failure and arrhythmia, among other cardiovascular diseases [19], [20], [21], [22], [23], [24], [25]. Here, we review the relationship between ERS and cardiovascular disease.
Drugs to suppress endoplasmic reticulum stress are important therapeutic strategies for cardiovascular diseases
ERS plays a vital role in promoting the occurrence and development of cardiovascular diseases. In addition, we describe a number of drugs that inhibit ERS, including hormone drugs, chemical drugs, polypeptide drugs, traditional Chinese medicine and others drugs, which may be necessary therapeutic strategies for the treatment of cardiovascular diseases (Table 1).
Conclusion
In this review, we introduce ERS/UPR and describe the relationship between ERS and cardiovascular diseases. In addition, hormone drugs, chemical drugs, polypeptide drugs, traditional Chinese medicine and others drugs that inhibit ERS are reviewed. Obviously, ERS-related proteins expression in cardiovascular diseases increased significantly. The stimulation of ERS promotes the occurrence and development of cardiovascular diseases, while the elimination of ERS saves cardiovascular diseases. More
Prospects
Up to now, cardiovascular diseases is still a common disease although various prevention strategies are widely used in clinical practice. As we are demonstrated in this paper, ERS-related accumulation of unfolded/misfolded proteins and UPR contribute to the cardiovascular diseases. There are several pieces of evidence supporting ERS in promoting the progression and development of cardiovascular diseases. In addition, hormone drugs, chemical drugs, polypeptide drugs, traditional Chinese medicine
Funding
This work was supported by the grants from the National Natural Science Foundation of China (Grant numbers: 81670265), and Innovation Platform Open Foundation of Education Department of Hunan province (Grant numbers: 18K073).
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Declaration of Competing Interest
The authors declare that there are no conflicts of interest.
References (116)
- et al.
ER stress and the unfolded protein response
Mutat. Res.
(2005) - et al.
Oxidative stress and the etiology of insulin resistance and type 2 diabetes
Free Radic. Biol. Med.
(2011) - et al.
ER stress-induced inflammation: does it aid or impede disease progression?
Trends Mol. Med.
(2012) - et al.
Translational control is required for the unfolded protein response and in vivo glucose homeostasis
Mol. Cell
(2001) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease
Cell
(2010)- et al.
IRE1, a double-edged sword in pre-miRNA slicing and cell death
Dev. Cell
(2012) - et al.
Protein kinase RNA-like endoplasmic reticulum kinase (PERK)/calcineurin signaling is a novel pathway regulating intracellular calcium accumulation which might be involved in ventricular arrhythmias in diabetic cardiomyopathy
Cell. Signal.
(2014) - et al.
Ischemia activates the ATF6 branch of the endoplasmic reticulum stress response
J. Biol. Chem.
(2009) - et al.
ER stress contributes to ischemia-induced cardiomyocyte apoptosis
Biochem. Biophys. Res. Commun.
(2006) - et al.
Macrophage miRNAs in atherosclerosis
Biochim. Biophys. Acta
(2016)
Protein kinase R-like endoplasmic reticulum kinase and glycogen synthase kinase-3alpha/beta regulate foam cell formation
J. Lipid Res.
Global burden of cardiovascular disease and stroke: hypertension at the core
Can. J. Cardiol.
Endoplasmic reticulum stress and protein quality control in diabetic cardiomyopathy
Biochim. Biophys. Acta Mol. Cell. Biol. Lipids
Irisin protects macrophages from oxidized low density lipoprotein-induced apoptosis by inhibiting the endoplasmic reticulum stress pathway
Saudi J. Biol. Sci.
The chemical chaperone 4-phenylbutyric acid attenuates pressure-overload cardiac hypertrophy by alleviating endoplasmic reticulum stress
Biochem. Biophys. Res. Commun.
Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor
Biochem. Biophys. Res. Commun.
Schisandrin B exhibits anti-inflammatory activity through modulation of the redox-sensitive transcription factors Nrf2 and NF-kappaB
Free Radic Biol. Med.
Cardiovascular risk reduction in diabetes: underemphasised and overdue. Messages from major trials
Clin. Med. (Lond.)
Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity
Cell
Endoplasmic reticulum dysfunction–a common denominator for cell injury in acute and degenerative diseases of the brain?
J. Neurochem.
Endoplasmic reticulum stress: relevance and therapeutics in central nervous system diseases
Mol. Neurobiol.
Regulation of apoptosis by endoplasmic reticulum pathways
Oncogene
Endoplasmic reticulum stress links oxidative stress to impaired pancreatic beta-cell function caused by human oxidized LDL
PLoS ONE
Endoplasmic reticulum stress regulates tumor growth and anti-tumor immunity: a promising opportunity for cancer immunotherapy
Cancer Immunol. Immunother.
Atmospheric pressure room temperature plasma jets facilitate oxidative and nitrative stress and lead to endoplasmic reticulum stress dependent apoptosis in HepG2 cells
PLoS ONE
Expression of endoplasmic reticulum stress markers GRP78 and CHOP induced by oxidative stress in blue light-mediated damage of A2E-containing retinal pigment epithelium cells
Ophthalmic Res.
The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies
Oncogene
Role of the unfolded protein response, GRP78 and GRP94 in organ homeostasis
J. Cell. Physiol.
Membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response
J. Cell Biol.
Unfolded protein response plays a critical role in heart damage after myocardial ischemia/reperfusion in rats
PLoS ONE
Endoplasmic reticulum stress affects lipid metabolism in atherosclerosis via CHOP activation and over-expression of miR-33
Cell. Physiol. Biochem.
Regulated expression of GRP78 during vasopressin-induced hypertrophy of heart-derived myocytes
J. Cell. Biochem.
Involvement of endoplasmic reticulum stress in uremic cardiomyopathy: protective effects of tauroursodeoxycholic acid
Cell. Physiol. Biochem.
Involvement of endoplasmic reticulum stress-associated apoptosis in a heart failure model induced by chronic myocardial ischemia
Int. J. Mol. Med.
Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6
Circ. Res.
Endoplasmic reticulum chaperone GRP78 protects heart from ischemia/reperfusion injury through Akt activation
Circ. Res.
MiR-33 contributes to the regulation of cholesterol homeostasis
Science
MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis
Science
MicroRNAs in cardiometabolic disease
Curr. Atheroscler. Rep.
The role of endoplasmic reticulum stress-glycogen synthase kinase-3 signaling in atherogenesis
Int. J. Mol. Sci.
Conditional knockout of macrophage PPARgamma increases atherosclerosis in C57BL/6 and low-density lipoprotein receptor-deficient mice
Arterioscler. Thromb. Vasc. Biol.
Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3
Nat. Immunol.
Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation
Nature
Ventricular hypertrophy and hypertension: prognostic elements and implications for management
Herz
Endoplasmic reticulum stress in the pathogenesis of hypertension
Exp. Physiol.
Endoplasmic reticulum stress is involved in cardiac damage and vascular endothelial dysfunction in hypertensive mice
Arterioscler. Thromb. Vasc. Biol.
Cited by (31)
Sarco/endoplasmic reticulum Ca<sup>2+</sup> ATPase (SERCA)-mediated ER stress crosstalk with autophagy is involved in tris(2-chloroethyl) phosphate stress-induced cardiac fibrosis
2022, Journal of Inorganic BiochemistryCitation Excerpt :When ER stress occurs, cells can maintain the synthesis of proteins by regulating the coordinated interaction between apoptosis and autophagy [19]. At the same time, ER stress can accelerate the expression of proinflammatory factors and oxidation (redox) imbalance, thus promoting the occurrence of cardiovascular diseases [20]. However, it is not clear whether ER stress is involved in OPFR-induced cardiotoxicity.
Crosstalk between the renin-angiotensin system and the endoplasmic reticulum stress in the cardiovascular system: Lessons learned so far
2021, Life SciencesCitation Excerpt :In Zhang et al. study, they have provided new insights into how the UPR could play a role in myocardial injury in an ischemia/reperfusion model, though CHOP-Caspase12 apoptosis pathway [54]. Finally, ER stress has also been linked to aggravated atherosclerosis pathology and accelerated occurrence of hypertension and cardiomyopathy [55], which also turns it into an important therapeutic target for treat CVD. The relationship between the RAS and the UPR signal transduction triggered by ER stress has not been fully explored.
Endoplasmic reticulum-targeting nanomedicines for cancer therapy
2021, Smart Materials in MedicineCitation Excerpt :The nucleus, mitochondrion, and plasma membrane are perhaps the most frequently investigated targets for the precise cell imaging and manipulation [6–10]. Recently, ER has increasingly been studied as an important cellular target due to its crucial role in many cellular activities and certain diseases [11–19]. ER is the intracellular endomembrane system that engages in many important cellular processes, such as the synthesis, processing, and intracellular transport of secreted and membrane-associated proteins [1], the synthesis and transport of lipids [20], and the maintenance of cellular calcium homeostasis [21].
Cardioprotection of pharmacological postconditioning on myocardial ischemia/reperfusion injury
2021, Life SciencesCitation Excerpt :ER dysfunction leads to inhibition of protein synthesis, protein refolding and clearance of misfolded proteins. After unfolded or misfolded proteins accumulate in the ER, the UPR is initiated and promotes apoptotic cell death [47]. Three main ER stress sensors activate the UPR, pancreatic endoplasmic reticulum kinase (PERK), glucose-regulating protein 78 (GRP78), activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE-1) [48].
In silico toxicity evaluation of Salubrinal and its analogues
2020, European Journal of Pharmaceutical SciencesCitation Excerpt :Endoplasmic reticulum (ER) stress as a molecular pathophysiological process leads to the appearance of diseases such as cancer (Urra et al., 2016; Oakes, 2020; Jaud et al., 2020; Yadav, 2014; Wang, 2014) myocardial infarction (Liu et al., 2016; Hong et al., 2017; Wang et al., 2018; Yang et al., 2020), neurodegenerative disorders (da Silva et al., 2020; Liu et al., 2019; Mou et al., 2020; Xiang et al., 2017; Remondelli and Renna, 2017; Sprenkle et al., 2017), diabetes mellitus (Ghosh et al., 2019; Back et al., 2012; Dong et al., 2017; Eizirik et al., 2008), diseases of the genitourinary system (Park et al., 2019; Cybulsky, 2017; Yum et al., 2017; Yan et al., 2018), disorders related to bone integrity (Gawron, 2016; Scheiber et al., 2019; Symoens et al., 2013; Navid and Colbert, 2017), etc. (Marciniak and Ron, 2006; Oakes and Papa, 2015; Barrera et al., 2018).
Resveratrol Inhibits Zinc Deficiency-Induced Mitophagy and Exerts Cardiac Cytoprotective Effects
2024, Biological Trace Element Research
- 1
Contributed equally to this work.