Original ArticleMMPs 2 and 9 are essential for coronary collateral growth and are prominently regulated by p38 MAPK
Highlights
► p38 MAPK is required for MMP 2/9 activity during coronary collateral growth (CG). ► MMP 2/9 activity is essential for extracellular matrix (ECM) degradation and CG. ► Lack of CG in metabolic syndrome correlates with lack of MMP 2/9 activity and reduced ECM degradation.
Introduction
Myocardial ischemia–reperfusion injury is a well-known phenomenon resulting from prolonged periods of ischemia followed by re-oxygenation. However, short, repetitive periods of ischemia followed by reperfusion can lead to adaptive responses and render the myocardium tolerant to longer periods of ischemia, in part through promoting collateral development [1]. Stable angina pectoris is a consequence of significant coronary artery constriction, and is characterized by transient periods of ischemia, upon increased myocardial metabolic demand followed by reperfusion at rest. Coronary collateral growth (CCG) is an adaptive response to transient, repetitive myocardial ischemia (RI). Clinically, patients with stable angina have a decreased incidence of fatal myocardial infarction, which is associated with better developed collateral networks [2]. In contrast, CCG has been shown to be severely impaired in patients suffering from type II diabetes [3] and the metabolic syndrome [4]. Likewise, CCG is impaired in our metabolic syndrome rat model (JCR:LA-cp or JCR) [5]. The JCR rat is obese, dyslipidemic (low HDL, high LDL, VLDL, and triglycerides) [5], insulin resistant with impaired glucose tolerance [6], and hypertensive [5], and thus, mimics the complex pathology of the human metabolic syndrome.
The process of CCG involves endothelial and vascular smooth muscle cell (VSMC) proliferation and migration, as well as extracellular matrix (ECM) remodeling. The early phase of collateral growth is associated with inward remodeling, in which cells migrate across the internal elastic lamina and the basement membrane, into the lumen of the pre-existing native collaterals. This is followed by outward remodeling in which cells migrate across the external elastic lamina into the vascular adventitia and the surrounding myocardium, thus allowing for vessel expansion and significant increases in blood flow [7], [8], [9]. Consequently, reorganization of the ECM, including ECM degradation, is a presumed integral part of collateral remodeling. However, direct measurements of this process during collateral growth have never been reported.
ECM degradation requires matrix metalloproteinases (MMPs), zinc-dependent endopeptidases capable of degrading extracellular matrix proteins. MMPs can be separated based on substrate specificity into interstitial collageneases (MMPs 1, 8 and 13), broad specificity MMPs (MMPs 3 and 7), metalloelastases (MMP 12), membrane-bound MMPs (MMP 14 (MT1-MMP) and MMP 17), and gelatinases (MMP 2 and 9). MMP 2 and 9 have been shown to degrade type IV collagen, laminin and elastin, the primary components of the vascular basement membrane and the internal and external elastic laminae, in vitro [10], [11], [12], [13]. They are known to play a role in cell proliferation, migration, differentiation, angiogenesis associated with cancer metasthesis, neointima formation following vascular injury and aneurysm formation and rupture [14], [15], [16]. Although degradation of the basement membrane and the vascular elastic laminae is a common aspect shared between these processes and collateral remodeling, they are not identical, and conclusions drawn from these studies do not uniformly apply to collateral growth. Increased MMP 2 and 9 expression has been associated with collateral growth, but the results are not entirely in agreement. In one study, during the early, inward remodeling phase in growing coronary collaterals, the neointima showed high expression of MMPs 2 and 9 while mature collaterals expressed low levels of these MMPs [17]. On the other hand, MMP 2 but not MMP 9 expression and activity were increased in mesenteric collateral vessels [18]. Importantly, a conclusive requirement for MMP 2 and 9 activation in CCG has not been shown. Furthermore, it is unknown whether MMP 2 and/or 9 regulation is altered in the metabolic syndrome, where CCG is impaired.
MMPs are regulated at the level of both expression and activation. Several signaling pathways have been shown to regulate MMP expression and/or activation. Among these are the mitogen activated protein kinases (MAPKs). MAPKs can be divided into the extracellular signal-regulated kinases (ERK1/2), p38 MAPK, and c-Jun N-terminal kinase (JNK) [19]. The ERK1/2 pathway has been shown to regulate expression and activation of many MMPs including MMP 9 [20]. p38 MAPK, when activated during inflammation or the innate immune response, lead to the activation of MMP 9 [21], and a single study implicates p38 MAPK in the regulation of MMP 9 activation in cultured airway smooth muscle cells [22]. However, it is not known which signaling pathways may regulate MMP expression and/or activation in collateral growth.
We have previously shown that transient p38 MAPK activation on day 3 of RI is required for CCG in the normal healthy rat model where inhibition of p38 MAPK resulted in ~ 60% reduction in RI-induced CCG [23]. In addition, we have shown that RI-induced CCG was severely compromised in the metabolic syndrome JCR rat model, and that this correlated with lack of RI-induced p38 MAPK activation [24]. However, the functional consequence of p38 MAPK activation in collateral growth remained unknown. Therefore the goals of this study were to determine: 1) whether RI-induced activation of p38 MAPK regulated the development of coronary collaterals through the activation of MMP 2 and 9 and the degradation of their ECM substrates, 2) whether MMP 2 and 9 were required for this ECM degradation and CCG, and 3) whether MMP 2 and/or 9 expression and/or activity were altered in the metabolic syndrome.
Section snippets
Rat model of coronary collateral growth/RI
Male, 10–12 week old Sprague–Dawley (SD) (300–350 g) or obese JCR:LA-cp rats (JCR) (650–700 g) were used for chronic implantation of a pneumatic occluder over the left anterior descending coronary artery (LAD), as described previously [25]. The RI protocol for rats consisted of 8 40s occlusions, one every 20 min over 2 h 20 min followed by a period of “rest” for 5 h 40 min. This 8 h cycle was repeated three times per day for 0–9 days. The specific inhibitors of p38 MAPK, SB203580 (3.2 mg/kg/day,
MMP 2 and 9 expression and activation are increased in response to repetitive ischemia in normal, healthy animals but not in the metabolic syndrome
No significant basal expression or activation of either MMP2 or 9 was observed in either rat phenotype. Western blot analysis demonstrated an increase in expression of MMP 2 and 9 in the SD animals specifically confined to the collateral dependent zone (CZ) on day 3 of the RI protocol (3.3 ± 0.3 fold vs. NZ for MMP 2; 3.6 ± 0.2 fold vs. NZ for MMP 9) (Fig. 1A). This increase in expression in the collateral dependent zone corroborates our previously published data that showed increased p38 MAPK
Discussion
The major novel findings in this study are that: 1) RI induces the expression and activation of MMP 2 and 9, which correlates with degradation of components of the basement membrane and the elastic laminae, type IV collagen, laminin and elastin, 2) RI-induced activation of MMP 2 and 9 is severely compromised in the metabolic syndrome, which is associated with the absence of type IV collagen, laminin and elastin degradation, 3) MMP 2 and 9 expression and activation by RI as well as type IV
Disclosure statement
None declared.
Acknowledgment
This study was supported by NIH R01 HL093052.
Glossary
- CCG
- coronary collateral growth
- CZ
- collateral-dependent zone, LAD perfusion territory
- ECM
- extracellular matrix
- ERK1/2 MAPK
- extracellular signal-regulated mitogen-activated protein kinase
- FGF
- fibroblast growth factor
- JNK MAPK
- c-Jun mitogen-activated protein kinase
- JCR
- Russell rat, JCR:LA-cp
- LAD
- left anterior descending coronary artery
- MK2
- mitogen-activated protein kinase activated protein kinase 2
- MMP
- matrix metalloproteinase
- NZ
- normal, non-ischemic zone
- p38 MAPK
- p38 mitogen-activated protein kinase
- RI
- repetitive ischemia
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2018, Journal of Molecular and Cellular CardiologyCitation Excerpt :So these findings indicate that MMP-2 and MMP-9 are the downstream targets of 15-LO/15-HETE pathway in vivo and in vitro. Previous studies have reported that the p38 MAPK signaling is involved in MMP-2 and MMP-9 activation [28]. We detected the expression of p-p38, p38 in NDGA treated cell.
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2018, Journal of Molecular and Cellular CardiologyCitation Excerpt :In our study, MMP2, MMP9, MMP3 or MMP7 are not involved in 20-HETE-dependent regulation of elastin degradation or regulation of arterial stiffness. This is consistent with our previous observations that activation of these MMPs is decreased in arteries from metabolic syndrome animals [48,89]. However, other elastases, for example cathepsin G from neutrophils, may play a role in elastin degradation.
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2016, Journal of Nutritional BiochemistryCitation Excerpt :Rather, the apparent but nonsignificant decline in collagen content relative to the nsECM of the arterial wall suggests that collagen is being replaced by another extracellular component. Given the close connection between p38MAPK and ECM production and degradation [36,39,40], this component may be a distinct ECM protein, matrix-metalloproteinase-degraded collagen or a combination of both, but at this point, its identity remains unknown. As well, it is possible that the nsECM consists of glycosaminoglycan, which has been shown to be increased in the aorta of SHR and decreased by a diet containing high levels of wild blueberry [41].