Abstract
Background
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a membrane protein
associated with apoptosis. Endoplasmic reticulum (ER) stress-induced apoptosis has
been determined in several cardiovascular diseases. Mitogen-activated protein kinase
(MAPK) signalling is involved in apoptosis. The aim of this study was to investigate
whether LOX-1, ER stress, and MAPKs play a role in cardiomyocyte apoptosis after coronary
microembolization (CME) and the exact mechanisms involved.
Methods
Thirty swine were randomized into the following groups (n = 5 per group): sham, CME,
CME + LOX-1 small-interfering RNA (siRNA), CME + control siRNA, CME + JNK inhibitor,
and CME + p38 inhibitor. The CME model was established by injecting microspheres into
the left anterior descending (LAD) artery, whereas swine in the sham group received
normal saline instead. Twelve hours after the sham operation or CME, cardiac function,
serum c-troponin I level, microinfarcts, and apoptotic index were determined. Relative
expression levels of LOX-1, ER stress markers (glucose-regulated protein 78 [GRP 78],
C/EBP homologous protein [CHOP], and cleaved caspase-12), cleaved caspase-3, c-Jun
NH2-terminal protein kinases (JNK), p38, and extracellular signal–related protein kinases
(ERK1/2) were measured.
Results
CME induced cardiac dysfunction, microinfarction, increased serum c-troponin I levels,
and cardiomyocyte apoptosis. Additionally, the expression of LOX-1, ER stress markers,
and cleaved caspase-3, and the phosphorylation of JNK, p38, and ERK1/2 were all enhanced.
LOX-1 siRNA inhibited these effects except the phosphorylation of ERK1/2. Pretreatment
with a JNK inhibitor or a p38 inhibitor attenuated the expression of ER stress markers
and apoptosis.
Conclusions
Our results indicated that CME induced cardiomyocyte apoptosis through the LOX-1–dependent
ER stress pathway, in which the phosphorylation of JNK and p38 were involved. This
might provide a new approach for the prevention and treatment of CME.
Résumé
Introduction
Le récepteur des lipoprotéines de basse densité oxydées de type lectine (LOX-1) est
une protéine membranaire associée à l’apoptose. L’apoptose induite par le stress du
réticulum endoplasmique (RE) a été déterminée dans plusieurs maladies cardiovasculaires.
La signalisation des protéines kinases activées par des agents mitogènes (MAPK) est
impliquée dans l’apoptose. Le but de cette étude était d’examiner si le LOX-1, le
stress du RE et les MAPK jouent un rôle dans l’apoptose des cardiomyocytes après la
micro-embolisation coronarienne (MEC) et les mécanismes exacts impliqués.
Méthodes
Trente porcs étaient répartis de manière aléatoire dans les groupes suivants (n =
5 par groupe) : traitement fictif, MEC + petit ARN interférent (ARNsi) LOX-1, MEC +
ARNsi témoin, MEC + inhibiteur de la protéine JNK (c-Jun N-terminal kinase) et MEC + inhibiteur de p38. Le modèle de MEC était établi en injectant les microsphères
dans la partie proximale de l’artère interventriculaire antérieure (AIA), alors que
les porcs du groupe de traitement fictif recevaient plutôt la solution saline habituelle.
Douze heures après l’opération simulée ou la MEC, la fonction cardiaque, le taux sérique
de troponine I cardiaque, les micro-infarctus et l’indice de l’apoptose étaient déterminés.
Les concentrations relatives de l’expression du LOX-1, des marqueurs de stress du
RE (la protéine régulée par le glucose 78 [GRP78], la protéine homologue C/EBP [CHOP]
et la caspase-12 clivée), de la caspase-3 clivée, des protéines kinases c-Jun NH2-terminal (JNK), des kinases p38 et des kinases régulées par les signaux extracellulaires
(ERK1/2) étaient mesurés.
Résultats
La MEC induisait la dysfonction cardiaque, le micro-infarctus, l’augmentation des
taux sériques de la troponine I cardiaque et l’apoptose des cardiomyocytes. De plus,
l’expression du LOX-1, des marqueurs de stress du RE et de la caspase-3 clivée, et
la phosphorylation de la JNK, de la p38 et de la ERK1/2 se sont toutes améliorées.
L’ARNsi LOX-1 inhibait ces effets, excepté la phosphorylation de la ERK1/2. Le prétraitement
par un inhibiteur de la JNK ou un inhibiteur de p38 atténuait l’expression des marqueurs
de stress du RE et de l’apoptose.
Conclusions
Nos résultats indiquaient que la MEC induisait l’apoptose des cardiomyocytes par la
voie dépendante du LOX-1 du stress du RE d’où la phosphorylation de la JNK et la phosphorylation
de la p38 étaient impliquées. Cela pourrait donner lieu à une nouvelle approche dans
la prévention et le traitement de la MEC.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Canadian Journal of CardiologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Coronary microembolization: from bedside to bench and back to bedside.Circulation. 2009; 120: 1822-1836
- Impact of atherosclerotic plaque composition on coronary microembolization during percutaneous coronary interventions.Basic Res Cardiol. 2008; 103: 587-597
- Incidence and clinical consequences of distal embolization on the coronary angiogram after percutaneous coronary intervention for ST-elevation myocardial infarction.Eur Heart J. 2009; 30: 908-915
- Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction.Circulation. 1998; 97: 765-772
- Impact of microvascular dysfunction on left ventricular remodeling and long-term clinical outcome after primary coronary angioplasty for acute myocardial infarction.Circulation. 2004; 109: 1121-1126
- Myocardial ‘no-reflow’—diagnosis, pathophysiology and treatment.Int J Cardiol. 2013; 167: 1798-1806
- TNF-alpha-induced cardiomyocyte apoptosis contributes to cardiac dysfunction after coronary microembolization in mini-pigs.J Cell Mol Med. 2014; 18: 1953-1963
- Effect of metoprolol on myocardial apoptosis and caspase-9 activation after coronary microembolization in rats.Exp Clin Cardiol. 2013; 18: 161-165
- Expression of lectin-like oxidized low-density lipoprotein receptors during ischemia-reperfusion and its role in determination of apoptosis and left ventricular dysfunction.J Am Coll Cardiol. 2003; 41: 1048-1055
- ER stress in cardiovascular disease.J Mol Cell Cardiol. 2010; 48: 1105-1110
- CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum.Genes Dev. 1998; 12: 982-995
- Pathological roles of MAPK signaling pathways in human diseases.Biochim Biophys Acta. 2010; 1802: 396-405
- the involvement of phosphatase and tensin homolog deleted on chromosome ten (PTEN) in the regulation of inflammation following coronary microembolization.Cell Physiol Biochem. 2014; 33: 1963-1974
- Blockade of NF-kappaB by pyrrolidine dithiocarbamate attenuates myocardial inflammatory response and ventricular dysfunction following coronary microembolization induced by homologous microthrombi in rats.Basic Res Cardiol. 2010; 105: 139-150
- Effect of atorvastatin (Lipitor) on myocardial apoptosis and caspase-8 activation following coronary microembolization.Cell Biochem Biophys. 2011; 61: 399-406
- Cardiomyocyte apoptosis and death receptor pathway in a rat model of coronary microembolization.Zhonghua Xin Xue Guan Bing Za Zhi. 2010; 38: 363-368
- Intracellular signaling of LOX-1 in endothelial cell apoptosis.Circ Res. 2009; 104: 566-568
- The discovery of LOX-1, its ligands and clinical significance.Cardiovasc Drugs Ther. 2011; 25: 379-391
- Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): a critical player in the development of atherosclerosis and related disorders.Cardiovasc Res. 2006; 69: 36-45
- Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions.Circulation. 1999; 99: 3110-3117
- Coronary microembolization: the role of TNF-alpha in contractile dysfunction.J Mol Cell Cardiol. 2002; 34: 51-62
- Role of apoptosis in cardiovascular disease.Apoptosis. 2009; 14: 536-548
- Ox-LDL induces endothelial cell apoptosis via the LOX-1-dependent endoplasmic reticulum stress pathway.Atherosclerosis. 2014; 235: 310-317
- Organelle-specific initiation of cell death pathways.Nat Cell Biol. 2001; 3: E255-E263
- Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis.Circulation. 2004; 110: 705-712
- Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1.Science. 2000; 287: 664-666
- IL-1beta induces ER stress in a JNK dependent manner that determines cell death in human pancreatic epithelial MIA PaCa-2 cells.Apoptosis. 2010; 15: 864-876
- Atorvastatin inhibits myocardial cell apoptosis in a rat model with post-myocardial infarction heart failure by downregulating ER stress response.Int J Med Sci. 2011; 8: 564-572
- Roles of p38 and JNK mitogen-activated protein kinase pathways during cantharidin-induced apoptosis in U937 cells.Biochem Pharmacol. 2004; 67: 1811-1818
- Signal transduction by the JNK group of MAP kinases.Cell. 2000; 103: 239-252
- Activation of lectin-like oxidized low-density lipoprotein receptor-1 induces apoptosis in cultured neonatal rat cardiac myocytes.Circulation. 2001; 104: 2948-2954
- SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase.Proc Natl Acad Sci U S A. 2001; 98: 13681-13686
- Establishment and characterization of an experimental model of coronary thrombotic microembolism in rats.Am J Pathol. 2010; 177: 1122-1130
Article info
Publication history
Published online: January 23, 2015
Accepted:
January 21,
2015
Received:
October 10,
2014
Footnotes
See page 1280 for disclosure information.
Identification
Copyright
© 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
