Angiotensin II induces an increase in MMP-2 expression in idiopathic ascending aortic aneurysm via AT1 receptor and JNK pathway

Abstract

The cellular and molecular mechanisms responsible for human idiopathic ascending aortic aneurysm (IAAA) remain unknown. Matrix metalloproteinase-2 (MMP-2) is a key enzyme for the degradation of extracellular matrix in aneurysmal walls. The aim of this study was to elucidate the role of the angiotensin II (Ang II) pathway in MMP-2 induction in IAAA aortic walls. Quantitative polymerase chain reaction and western blot analysis were used to compare the MMP-2 mRNA and protein levels in ascending aortic specimens with those in IAAA patients (n = 10) and heart transplant donors (n = 5) without any aortopathy. It was found that MMP-2 expression was significantly increased, which was associated with elastic lamellae disruption in IAAA walls. Additionally, the expression levels of angiotensinogen (AGT) and Ang II in the ascending aortic tissues from individuals with and without IAAAs were detected by western blot analysis and radioimmunoassay, respectively. The results demonstrated that the expressions of AGT and Ang II protein were significantly increased in the ascending aortic tissues of IAAA patients. Furthermore, whether Ang II induces MMP-2 expression was investigated using human IAAA walls ex vivo culture. It was found that exogenous Ang II increased the MMP-2 expression in a dose-dependent manner, which was completely inhibited by the Ang II type 1 receptor (AT1R) inhibitor candesartan and was mediated by c-Jun N-terminal kinase (JNK) activation. Taken together, these results indicate that Ang II can induce an increase of MMP-2 expression via AT1R and JNK in ex vivo cultured IAAA aortic walls, and suggest that angiotensin receptor blocker (ARB) drugs and JNK inhibitors have the potential in the prevention or treatment of IAAAs.

Differential regulation of matrix metalloproteinases in varicella zoster virus-infected human brain vascular adventitial fibroblasts

“…MMP-9 is also elevated in the superficial temporal arteries of patients with giant cell arteritis [11], a disease recently linked with VZV infection [12]. Interestingly, while increased MMP-2 has been found in intracranial [13] and abdominal aortic aneurysms [14,15] compared to controls, we found decreased expression of MMP-2 in VZV-infected BRAFs. A similar pattern of decreased MMP-2 and increased MMP-1 and 9 has been described in chronic thoracic aortic dissection [16].…”

Strategies for Pharmacological Organoprotection during Extracorporeal Circulation Targeting Ischemia-Reperfusion Injury

“…Moreover, they influence cytokine processing for example activation of TNFα or IL-1β, thereby modulating leucocyte recruitment and inflammatory processes (Van Lint and Libert, 2007 ). A variety of cardiovascular diseases are related to a dysfunction of MMPs: the development of aortic aneurysms which was ascribed to a MMP-17 deficiency, or an over activation of MMP-2, plaque vulnerability in patients with angina pectoris, as well as impaired wound healing in patients suffering from diabetes mellitus (Chen et al, 2015b ; Martin-Alonso et al, 2015 ; Uccioli et al, 2015 ; Wang et al, 2015 ). Opponents of the MMPs are the TIMPs (tissue inhibitors of metalloproteinases) from which four different inhibitors are known.…”

Tendon Healing in a Mouse Model of Loeys-Dietz Syndrome: Controlled Study Using a Patellar Tendon Transection Model

“…Increased MMP activity has been associated with deterioration of ECM integrity. MMP2 levels have been positively correlated with the severity/size of aortic aneurysms in both animal models and patients, suggesting that MMP dysregulation may play a key role in loss of connective tissue integrity 12,13. Similarly, elevated MMP expression has also been shown to predispose to tendinopathies and tendon transection,14,15 and MMP-2 activation after tendon tearing correlates with ECM degradation in regenerating tissue in both animal models and patients 16,17.…”