Current progress of the inflammasomes in aortic aneurysm and aortic
dissection
Jun Cui
1, Fang Bian
21. Department of Cardiothoracic Surgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei Xiangyang 441021;
2. Department of Pharmacology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei Xiangyang 441021
Journal of Hainan Medical University
http://www.hnykdxxb.com
ARTICLE INFO ABSTRACT
Article history: Received 27 May 2018
Received in revised form 2 Jun 2018 Accepted 8 Jun 2018
Available online 14 Jun 2018
Keywords:
Essential hypertension ECG Cornell voltage Left ventricle hypertrophy
Corresponding author: Bian Fang (1985-), Ph.D., Department of Pharmacology,
Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei Xiangyang 441021)。
E-mail: [email protected]
Fund Project: This work was supported by grants from the National Natural Science (grant NO.: 81503072).
1. Introduction
Aortic aneurysm (AA) is generally defined as a permanent and irreversible dilation of aorta exceeding the normal diameter by at least 50%, which is a degenerative cardiovascular disease (CVD). Large AA diameters are associated with increased risk of aneurysm rupture. It is estimated that AA occurred in approximately 13 000 patients in the United States annually and it is currently the 15
leading cause of death for patients ≥65 years. A recent study showed
that high sensitivity C-reactive protein (hsCRP) together with C-C family chemokines, eotaxin and RANTES, had potential utility as abdominal aorta aneurysm (AAA) biomarkers[1]. Aortic dissection (AD) is the most devastating complication of aortic diseases. According to population-based studies, the annual incidence ranged from 6/100 000 in a British study, to 9.1/100 000 in women or 16.3/100 000 in men in a Swedish study. Evidence has been revealed
risk factors for dissection, including aneurysmal diseases and genetic disorders. Moreover, several plasma markers were studied as potential candidates for AD biomarkers, involving D-dimer, BB-isozyme of creatine kinase, calponin, elastin and so on.
Generally, surgical therapy and endovascular repair were used to treat AA and AD. Surgical therapy is highly effective in preventing death by rupture for larger AAs. However, surgery is costly and related with high morbidity and mortality. Endovascular repair is with lower postoperative mortality and complications compared to surgical repair, while there are no significant differences in mortality in the long term due to a higher incidence of re-intervention in endovascular repair. There is no doubt that inflammation has critical roles on the pathogenesis of AA and AD. Inflammasome, a large multi-protein complex in the cytosol regulating interleukin-1β (IL-1β) production, has critical roles on the pathogenesis of various cardiovascular diseases, such as myocardial reperfusion injury, atherosclerosis, vascular injury. However, the special roles of the inflammasome in AA and AD need further studies. This review aims to summarize the current progress of the inflammasomes on AA/AD-related proteins and signal pathways to further explore the role of the inflammasomes in the progression of AA and AD.
Objective:ToAortic aneurysm (AA) is the permanent, irreversible, asymmetrical arterial
2. AA and AD
AAA is estimated to contribute to about 2%-4% in men ≥65 years,
while thoracic aortic aneurysm (TAA) occurs at the most lethal site for arterial dilatation and at a rate of 4.5-5.9/100,000 person years. Embryological aetiologies, evolution progresses and pathological features between AAA and TAA are different.
TAA has strong hereditary influence and occurs commonly at younger ages with no obvious correlation with gender. At the pathological level, TAA is characterized by elastic fibers fragmentation, VSMCs loss, proteoglycan deposition and a less remarkable inflammatory cells infiltration . In patients with TAA, the Notch signaling was up-regulated in fibroblasts , while was down-regulated in VSMCs[2]. MiR-29b was found increased in TAA, which mediated downregulation of extra cellular matrix (ECM) proteins [3]
and regulated aortic wall apoptosis[4]. No variation of miR-21 was observed in TAA animal models.
The risk factors associated with AAA include increasing age, male sex and lifestyle-related risk factors, like smoking, hypertension and hypercholesterolemia. Three pathological marks are displayed in the progression of AAA: ECM degradation, VSMCs loss and infiltration of macrophages, neutrophils, mast cells and T/B lymphocytes. In AAA, increased activity of matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, participated in the degradation of elastic fibers, which eventually led to the gradual weakening and dilation of the aorta. Transforming growth factor (TGF)-β signaling is able to up-regulate MMP activity. There are two TGF-β signaling pathways involved in aneurysm formation[5]. Moreover, another two proteases, serine proteases and cysteine proteases, are also reported to augment degradation of ECM contents, such as different collagen isoforms (e.g., type I and III collagen) and elastin[6,7]. In addition, the Notch signaling is found to inhibit the development of AAA[8]. Some miRNAs were identified in up-regulating (e.g., miR-155/-146a/-223/-516a-5p) or down-regulating (e.g., miR-24/-133a/-30c-2) or unchanging (e.g., miR-133b/-29b) in human aneurysmal tissues, which were involved in aneurysm formation and complications[9]. The most feared clinical consequence of AA progression is acute rupture, which carries a mortality of 80%. The risk factors for AD mainly include: medial degeneration-related risk factors, like Marfan syndrome, Loeys-Dietz syndrome, inflammatory diseases of the aorta, bicuspid aortic valve and family TAA; increasing aortic wall stress-associated risk factors, like hypertension and physical trauma.
3. Inflammation and AA/AD
Extensive research has demonstrated that inflammation is involved in the development of AA and AD. Animal and human pathology studies showed that aneurysm initiation involved a local inflammatory response with subsequent infiltration of monocyte/ macrophages, polymorphonuclear leukocytes, and T/B lymphocytes. In AAA patients, it was found that a large number of inflammatory cytokines, such as TNF-α, TGF-β, IL-1β, and IL-6/-17/IL-23, were markedly increased. Of note, miRNAs related to VSMC apotosis (miR-21/-221/-222) inflammation (miR-124a, 146a, 155 and 223) were markedly elevated in tissues from AAA patients, while miRNAs related to inflammation in serum decreased significantly[10].
Statins have been suggested to suppress MMP-9 and chemokine secretion in human AAA, which would attenuate AAA progression[11]. Peroxisome proliferator-activated receptor (PPAR)-γ agonist was found to inhibit inflammation in AA patients, as demonstrated by significantly decreasing the levels of TNF-α
AD-induced adventitial CXCL1/granulocyte-colony stimulating factor expression facilitated local neutrophils recruitment and activation, which triggered adventitial inflammation via high levels of IL-6. Furthermore, IL-6 expression triggered aortic expansion and ruptur[20-22]. It was found that omega-3 polyunsaturated fatty acids (n-3 PUFAs) enabled to protect the mice against inflammatory and oxidative stress responses, which would reduce the incidence of aortic rupture in Ang II-infused Apoe-/-mice[23]. The number of neutrophils and macrophages infiltrating the abdominal aorta were significantly decreased after feeding with high n-3 PUFAs diet. In addition, the catalytic subunit of nicotinamide-adenine dinucleotide phosphate oxidase (NOX) and superoxide activity were also markedly attenuated. Ferrari and co-workers showed that ROS modulated the synthetic VSMC phenotype via connective tissue growth factor (CTGF) expression in TAA, which would increase the risk of aortic dissection and rupture[24]. S1001A12, a pro-inflammatory protein, would increase the risk of AD and complications by promoting oxidative stress-mediated VSMCs apoptosis[25]. Recently, it was found that ursodeoxycholic acid would prevent AD formation by down-regulating oxidative stress induced by VSMCs apoptosis via inhibiting NOX subunits (p47, p67 and gp91) expression, increasing Nrf2 expression, and rescuing redox enzymes (Cu/Zn-SOD, Mn-SOD and CAT) activity[26].
4. Inflammasome and AA/AD
Inflammasome is a large multiprotein complex, which contains a pattern recognition receptor (PRR), typically the NLR or an absent in melanoma 2 (AIM2)-like receptor family. Currently, NLRP3 inflammasome is the most extensively studied inflammasome type, which is composed of senior protein NLRP3, adaptor protein ASC (Apoptosis associated speck-like protein containing a CARD) and inflammation related to protein kinase Pro-caspase-1. An accumulating body of evidence has shown that the inflammasome plays a key role in the pathogenesis of cardiovascular disease, including myocardial ischemia-reperfusion injury, vascular injury, atherosclerosis. Therefore, the inflammasome may participate in AA and AD formation.
In AAA patients, IL-1β protein was increased 4-fold and gene expression was significantly elevated over 10-fold in aortas[27], as well as serum IL-1β was increased nearly 10-fold[28]. Correspondingly, IL-1β protein was reported to be about 20-fold in human TAA[29]. Inhibition of IL-1β by genetic depletion or pharmacological receptors (IL-1 receptor antagonist or caspase inhibitor) was able to prevent AAA and TAA formation by reducing the number of macrophage and MMP-9 expression[29]. Evidence showed that IL-1β could stimulate VSMCs and macrophages to
produce MMP-9[30,31]. In vitro study by Wu et al. indicated that MMP-9 could be directly activated by NLRP3 inflammasome in thoracic aortic SMCs. Co-immunoprecipitation analysis observed MMP-9 binding to NLRP3 inflammasome[32]. In addition, IL-1β
accelerated the initial and progression of human TAA and TAD by up-regulating the expression of MMP-9 in aortic media cells[32]. Moreover, Jing and co-workers has also reported that overexpression of IL-1β and IFN-γ in type I TAD and ascending thoracic aortic aneurysms (ATAA) is correlated with MMP-9 expression and aortic media cells apoptosis in human[33].
It was reported that NLRP3 inflammasome play an important role in the pathophysiology of AAA[34]. It was investigated that after challenged with a high-fat diet and infused with Ang II, NLRP3-/- mice and glyburide-treated WT mice have significantly lower incidences of AA and AD. Meantime, in Apoe-/- mice, glyburide can decrease levels of NLRP3, ASC and caspase-1 and prevent AA/AD formation[35]. Recently, evidence showed that NLRP3-/-Apoe-/-, ASC-NLRP3-/-Apoe-/-, Caspase-1-/-Apoe-/- mice exhibited a decrease in the incidence and severity of Ang II-induced AAA as compared to Apoe-/- mice. Furthermore, these mice displayed decreased inflammatory cells infiltration, elastic lamina degradation and MMP (MMP-2/9) activation in the arteries [36]. Compared to normal aortas, NLRP3 expression was much higher especially in de-differentiated VSMCs and inflammatory cells in TAA and TAD patients, which exhibited serious vascular inflammation and tissue destruction[37]. A recent study revealed that expressions of NLRP3, Caspase-1 and IL-1β were much higher in aneurysmal lesions of hyperhomocysteinemia (HHcy)-aggravated AAA formation[36]. Folic acid administration or lentiviral silencing of NLRP3 dramatically ameliorated HHcy-exaggerated AAA formation through inhibiting NLRP3 inflammasome activation. They further confirmed that increased mitochondrial ROS and TGF-β signaling were involved in NLRP3 inflammasome activation. Wang et al. also revealed that NLRP3 would affect expressions of TGF-β-responsive genes including MMP-9[38]. Additionally, NLRP3-/- mice treated with Ang II significantly decreased levels of TGF-β and SM-22-α in VSMCs,
along with transformation of VSMCs into fibroblasts in particular ascending aorta[39].
could release extensive endogenous ATP.
In summary, many investigations demonstrate that the inflammasome is tightly involved in the development of AA and AD, which may be helpful to explore new biomarkers and therapeutic targets.
References
[1] Jones GT, Phillips LV, Williams MJ. Two CC. Family chemokines,
eotaxin and RANTES, are novel independent plasma biomarkers for
abdominal aortic aneurysm. J Am Heart Assoc 2016; 5: e002993.
[2] McKellar SH, Tester DJ, Yagubyan M. Novel NOTCH1 mutations in
patients with bicuspid aortic valve disease and thoracic aortic aneurysms. J Thoracic Cardiovasc Surg 2007; 134: 290-296.
[3] Boon RA, Seeger T, Heydt S. MicroRNA-29 in aortic dilation:
implications for aneurysm formation. Circ Res 2011; 109: 1115-1119.
[4] Merk DR, Chin JT, Dake BA. miR-29b participates in early aneurysm
development in Marfan syndrome. Circ Res 2012; 110: 312-324.
[5] Holm TM, Habashi JP, Doyle JJ. Noncanonical TGF-β signaling
contributes to aortic aneurysm progression in Marfan syndrome mice. Science 2011; 332: 358-361.
[6] Shimizu K, Mitchell RN, Libby P. Inflammation and cellular immune
responses in abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol
2006; 26: 987-994.
[7] Manning MW, Cassis LA, Daugherty A. Differential effects of
doxycycline, a broad-spectrum matrix metalloproteinase inhibitor, on
angiotensin II-induced atherosclerosis and abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 2003; 23: 483-488.
[8] Wang YW, Re HL, Wang HF. Combining detection of Notch1 and tumor
necrosis factor-毩 converting enzyme is a reliable biomarker for the
diagnosis of abdominal aortic aneurysms. Life Sci 201; 127: 39-45.
[9] Raffort J, Lareyre F, Clement M. Micro-RNAs in abdominal aortic
aneurysms: insights from animal models and relevance to human disease. Cardiovasc Res 2016; 110: 165-177.
[10] Kin K, Miyagawa S, Fukushima S. Tissue- and plasma-specific
MicroRNA signatures for atherosclerotic abdominal aortic aneurysm. J Am Heart Assoc 2012; 1: e000745.
[11] Yoshimura K, Nagasawa A, Kudo J. Inhibitory effect of statins on
inflammation-related pathways in human abdominal aortic aneurysm
tissue. Int J Mol Sci 2015; 16: 11213-11228.
[12] Motoki T, Kurobe H, Hirata Y. PPAR-γ agonist attenuates inflammation
in aortic aneurysm patients. Gen Thorac Cardiovasc Surg 2015; 63:
565-71.
[13] Kaneko H, Anzai T, Morisawa M. Resveratrol prevents the development
of abdominal aortic aneurysm through attenuation of inflammation,
oxidative stress, and neovascularization. Atherosclerosis 2011; 17:
350-357.
[14] Ren H, Li F, Tian C. Inhibition of proteasome activity by Low-dose
Bortezomib attenuates angiotensin II-induced abdominal aortic aneurysm
in Apo E(-/-) mice. Sci Rep 2015; 5: 15730.
[15] Vorkapic E, Dugic E, Vikingsson S. Imatinib treatment attenuates growth
and inflammation of angiotensin II induced abdominal aortic aneurysm. Atherosclerosis 2016; 249: 101-109.
[16] Sharma AK, Salmon MD, Lu G. Mesenchymal stem cells attenuate
NADPH oxidase-dependent high mobility group box 1 production and
inhibit abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 2016;
36: 908-918.
[17] Yan YW, Fan J, Bai SL. Zinc prevents abdominal aortic aneurysm
formation by induction of A20-mediated suppression of NF-κB
pathway. PLoS One 2016; 11: e0148536.
[18] Sugano Y, Anzai T, Yoshikawa T. Serum C-reactive protein elevation
predicts poor clinical outcome in patients with distal type acute aortic
dissection: association with the occurrence of oxygenation impairment. Int J Cardiol 2005; 102: 39-45.
[19] Kurabayashi M, Okishige K, Azegami K. Reduction of the PaO2/
FiO2 ratio in acute aortic dissection-relationship between the extent of
dissection and inflammation. 2010; 74: 2066-2073.
[20] Anzai A, Shimoda M, Endo J. Adventitial CXCL1/G-CSF expression in
response to acute aortic dissection triggers local neutrophil recruitment
and activation leading to aortic rupture. Circ Res 2015; 116: 612-623.
[21] Ju X, Ijaz T, Sun H. IL-6 regulates extracellular matrix remodeling
associated with aortic dilation in a fibrillin-1 hypomorphic mgR/mgR
mouse model of severe Marfan syndrome. J Am Heart Assoc 2014; 3(1):
e000476.
[22] Tieu, BC, Lee C, Sun H. An adventitial IL-6/MCP1 amplification loop
accelerates macrophage-mediated vascular inflammation leading to aortic
dissection in mice. J Clin Invest 2009; 119: 3637-3651.
[23] Wales KM, Kavazos K, Nataatmadja M. N-3 PUFAs protect against
aortic inflammation and oxidative stress in angiotensin II-infused
apolipoprotein E-/- mice. PLoS One 2014; 9: e112816.
[24] Branchetti E, Poggio P, Sainger R. Oxidative stress modulates vascular
smooth muscle cell phenotype via CTGF in thoracic aortic aneurysm. Cardiovasc Res 2013;100: 316-24.
[25] Das D, Gawdzik J, Dellefave-Castillo L. S100A12 expression in thoracic
aortic aneurysm is associated with increased risk of dissection and
perioperative complications. J Am Coll Cardiol 2012; 60: 775-785.
[26] Liu W, Wang B, Wang T. Ursodeoxycholic acid attenuates acute aortic
dissection formation in angiotensin ii-infused apolipoprotein e-deficient
mice associated with reduced ros and increased nrf2 levels. Cell Physiol Biochem 2016, 38: 1391-1405.
[27] Abdul-Hussien H, Hanemaaijer R, Kleemann R. The pathophysiology
of abdominal aortic aneurysm growth: corresponding and discordant
inflammatory and proteolytic processes in abdominal aortic and popliteal
artery aneurysms. J Vascular Surg 2010; 51: 1479-1487.
Arterioscler Thromb Vasc Biol 1997; 17: 2843-2847.
[29] Johnston WF, Salmon M, Pope NH. Inhibition of interleukin-1beta
decreases aneurysm formation and progression in a novel model of
thoracic aortic aneurysms. Circulation 2014; 130: S51-S59.
[30] Gurjar MV, Deleon J, Sharma RV. Role of reactive oxygen species in
IL-1 beta-stimulated sustained ERK activation and MMP-9 induction.
American journal of physiology. Am J Physiol Heart Circ Physiol 2001;
281: H2568-H2574.
[31] Liang KC, Lee CW, Lin WN. Interleukin-1beta induces MMP-9
expression via p42/p44 MAPK, p38 MAPK, JNK, and nuclear
factor-kappaB signaling pathways in human tracheal smooth muscle cells, J Cell Physiol 2007; 211: 759-770.
[32] Wu D, Choi JC, Coselli J. NLRP3 inflammasome activates matrix
metalloproteinase-9: potential role in smooth muscle cell dysfunction in
thoracic aortic disease. J Surg Res 2013; 179: p204.
[33] Zhang L, Liao MF, Tian L. Overexpression of interleukin-1beta
and interferon-gamma in type I thoracic aortic dissections and
ascending thoracic aortic aneurysms: possible correlation with matrix
metalloproteinase-9 expression and apoptosis of aortic media cells. Eur J Cardiothorac Surg 2011; 40: 17-22.
[34] Roberts RL, Van Rij AM, Phillips LV. Interaction of the inflammasome
genes CARD8 and NLRP3 in abdominal aortic aneurysms. Atherosclerosis
2011; 218: 123-126.
[35] Wu D, Zheng Y, Choi JC. Blockade of the NLRP3 inflammasome
cascade prevents thoracic aortic aneurysm and dissection formation. Journal of Surgical Research 2014; 186: p521–522.
[36] Sun W, Pang Y, Liu Z. Macrophage inflammasome mediates
hyperhomocysteinemia-aggravated abdominal aortic aneurysm. J Mol Cell Cardiol 2015; 81: 96-106.
Thoracic Aortic Aneurysms and Dissections. J Surg Res 2012; 172: p280.
[38] Wang W, Wang X, Chun J. Inflammasome-independent NLRP3
augments TGF-beta signaling in kidney epithelium. J Immunol 2013;
190: 1239-1249.
[39] Choi JC, Wu D, Zheng Y. Activation of the NLRP3 inflammasome
cascade amplifies TGFb signaling during acute ascending aortic stress. J Surg Res 2014; 186: 597.
[40] DihlmannS, Erhart P, Mehrabi A. Increased expression and activation
of absent in melanoma 2 inflammasome components in lymphocytic
infiltrates of abdominal aortic aneurysms. Mol Med 2014; 20: 230-237.
[41] Duewell P, Kono H, Rayner KL. NLRP3 inflammasomes are required
for atherogenesis and activated by cholesterol crystals. Nature 2010; 464:
1357-1361.
[42] Razani B, Feng C, Coleman T. Autophagy links inflammasomes to
atherosclerotic rogression. Cell Metab 2012; 15: 534-544.
[43] Zheng Y, Gardner SE, Clarke MC. Cell death, damage-associated
molecular patterns, and sterile inflammation in cardiovascular disease. Arterioscler Thromb Vasc Biol 2011; 31: 2781-2786.
[44] G e r t z S D , G av i s h L , M i n t z Y. C o n t r a d i c t o r y e ff e c t s o f
hypercholesterolemia and diabetes mellitus on the progression of
abdominal aortic aneurysm. Am J Cardiol 2015; 115: 399-401.
[45] Pawlikowski M, Pfitzner R, Skinner C. Mineral-cholesterol
concentrations of the aortic aneurysmatic wall. Pol J Pathol 1996; 47:
225-232.
[46] Wang Y, Zhao ZM, Zhang GX. Dynamic autophagic activity affected
the development of thoracic aortic dissection by regulating functional
properties of smooth muscle cells. Biochem Biophys Res Commun 2016;
