Angiotensin II increases matrix metalloproteinase 2 expression in human aortic smooth muscle cells via AT1R and ERK1/2

Abstract

Increased levels of angiotensin II (Ang II) and activated matrix metalloproteinase 2 (MMP-2) produced by human aortic smooth muscle cells (human ASMCs) have recently been implicated in the pathogenesis of thoracic aortic aneurysm (TAA). Additionally, angiotensin II type 1 receptor (AT1R)-mediated extracellular signal-regulated kinase (ERK)1/2 activation contributes to TAA development in Marfan Syndrome. However, there is scant data regarding the relationship between Ang II and MMP-2 expression in human ASMCs. Therefore, we investigated the effect of Ang II on MMP-2 expression in human ASMCs and used Western blotting to identify the Ang II receptors and intracellular signaling pathways involved. Reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence data demonstrated that Ang II receptors were expressed on human ASMCs. Additionally, Ang II increased the expression of Ang II type 2 receptor (AT2R) but not AT1R at both the transcriptional and translational levels. Furthermore, Western blotting showed that Ang II increased MMP-2 expression in human ASMCs in a dose-and time-dependent manner. This response was completely inhibited by the AT1R inhibitor candesartan but not by the AT2R blocker PD123319. In addition, Ang II-induced upregulation of MMP-2 was mediated by the activation of ERK1/2, whereas p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) had no effect on this process. In conclusion, these results indicate that Ang II can increase the expression of MMP-2 via AT1 receptor and ERK1/2 signaling pathways in human ASMCs and suggest that antagonists of AT1R and ERK1/2 may be useful for treating TAAs.Keywords: Angiotensin II, renin angiotensin system, matrix metalloproteinase-2, extracellular signal-regulated kinase 1/2, human aortic smooth muscle cells 2015; 240: 1564-1571. Experimental Biology and Medicine

Endothelial Mineralocorticoid Receptor Mediates Parenchymal Arteriole and Posterior Cerebral Artery Remodeling During Angiotensin II–Induced Hypertension

“…S9 A, M). Previous studies have shown that AngII-hypertension increases the expression of MMP-2 in the aorta and in VSMC and that this is important for the process of arterial remodeling 13, 14 . Consistent with these previous findings, AngII treatment significantly increased the mRNA expression of MMP-2 in the PCA and this appears to be mediated, at least in part, by MR signaling as EPL prevented the increase (Fig.…”

Loss of MURC/Cavin-4 induces JNK and MMP-9 activity enhancement in vascular smooth muscle cells and exacerbates abdominal aortic aneurysm

“…4C). Although Ang II-induced ERK activation activates the activity of MMP-2 in VSMCs [23], the ERK activation in MURC/Cavin-4 knockdown VSMCs was significantly reduced (Fig. 4D).…”

“…In addition to JNK, extracellular signal-regulated kinase (ERK) is also involved in AAA formation [31]. Ang II induces ERK activation resulting in an increase of MMP-2 expression in VSMCs [23]. MURC/Cavin-4 knockdown suppresses phenylephrine-induced ERK activation in cardiomyocytes [21].…”

Sex differences in abdominal aortic aneurysms

“…In support of these findings, an ex vivo study on VSMCs demonstrated that the absence of estrogen resulted in the upregulation of AT 1 Rs, whereas the presence of estrogen reversed this effect (136). On the basis of these findings showing a role of ANG II activation of AT 1 R in AAA pathogenesis (191), estrogen downregulation of these RAAS constituents likely protects against AAA.…”