Insulin‐like growth factor‐binding protein 3 inhibits angiotensin II‐induced aortic smooth muscle cell phenotypic switch and matrix metalloproteinase expression

Abstract

New Findings What is the central question of this study?Insulin‐like growth factor 1 and its major binding protein insulin‐like growth factor binding protein 3 (IGFBP3) are involved in collagen deregulation in several cardiovascular diseases: what is the role of IGFBP3 in thoracic aortic dissection and does it regulate aortic smooth muscle cells’ phenotypic switch? What is the main finding and its importance?IGFBP3 inhibits aortic smooth muscle cells’ phenotypic switch from a contractile to a synthetic phenotype, decreases matrix metalloproteinase 9 activation and suppresses elastin degradation. These findings provide a better understanding of the pathogenesis of thoracic aortic dissection. Abstract Thoracic aortic dissection (TAD) is characterized by aortic media degeneration and is a highly lethal disease. An aortic smooth muscle cell (AoSMC) phenotypic switch is considered a key pathophysiological change in TAD. Insulin‐like growth factor binding protein 3 (IGFBP3) was found to be downregulated in aortic tissues of TAD patients. The present work aimed to study the function of IGFBP3 in AoSMCs’ phenotypic switch and matrix metalloproteinase (MMP) expression. We established a mouse model of TAD by angiotensin (Ang) II infusion to β‐aminopropionitrile‐administrated mice, and found decreased IGFBP3 expression accompanied by aortic dilatation and elastin degradation in vivo. Further, mouse (m)AoSMCs were isolated from mouse thoracic aorta and treated with Ang II. Ang II induced downregulation of IGFBP3 in vitro. To further study the function of IGFBP3, primary mAoSMCs were infected with adenovirus expressing IGFBP3 followed by Ang II induction. Enforced upregulation of IGFBP3 decreased MMP9 expression and activation as well as increasing tissue inhibitor of metalloproteinase (TIMP) 1 expression in Ang II‐induced mAoSMCs. No difference was observed in MMP2 and TIMP3 expression. IGFBP3 suppressed subsequent Ang II‐induced elastin degradation in vitro. IGFBP3 inhibited Ang II‐induced mAoSMCs’ phenotypic switch as evidenced by increased smooth muscle actin α‐2 (ACTA2) and myosin heavy chain 11 (MYH11) expression and decreased secreted phosphoprotein 1 (SPP1) and vimentin expression. Taken together, the present study demonstrates the role of IGFBP3 in preserving AoSMCs’ contractile state and reducing MMP9 activation and thus promoting elastic fibre synthesis, which provides a better understanding of the pathogenesis of TAD.

Sustained Downregulation of Vascular Smooth Muscle Acta2 After Transient Angiotensin II Infusion: A New Model of “Vascular Memory”

“…Through AT 1 R, AngII stimulation produces changes in the contractile machinery, constisting in decreased expression of contractiles markers such as αSMA (ACTA2), SM22a (TAGLN), and SMMHC (MYH11) (9,46). As others (41,47), in parallel with vascular remodeling, we observed significant changes in contractile markers expression in aortas under AngII infusion, with downregulation of "vascular smooth muscle contraction" pathway, and ACTA2 expression, but also TAGLN and MYH11 (see raw data). In addition, this phenotypic switch was maintained in time despite the end of AngII stimulation, for the "vascular smooth muscle contraction pathway", and also for αSMA expression, both at mRNA and protein levels (Figures 4B, 5A).…”

“…Mutations in this gene cause a variety of vascular diseases, such as thoracic dilated aortic disease, coronary artery disease, stroke, and Moyamoya disease (39), and also multisytemic smooth muscle dysfunction syndrome (40). Downregulation of αSMA expression induced by AngII has also been described in vascular SMC in vitro (41,42).…”

Upregulated IGFBP3 with Aging Is Involved in Modulating Apoptosis, Oxidative Stress, and Fibrosis: A Target of Age-Related Erectile Dysfunction

“…MMPs form a key family of proteolytic enzymes that participate in tissue remodeling by degrading ECM and basement membrane components. Chen et al revealed that MMP9 expression in aortic SMCs can be induced by Ang II and that overexpression of IGFBP3 can reduce the expression of MMP9 [ 40 ]. Suppressing IGFBP3 expression in mice with diabetic cardiomyopathy can alleviate cardiac fibrosis and enhance cell proliferation while inducing AKT and ERK phosphorylation [ 41 ]; this potentially plausible signaling pathway needs to be explored further.…”

Stimulus-Responsive Zwitterionic Prodrug Delivery System with Sustained Release of Hydrogen Sulfide for Protective Aortic Dissection

“…Classically, animal models of Ang II-infusion are the characterized and widely used models of abdominal aortic aneurysms or aortic dissections . In addition, the effect of Ang II on smooth muscle cell phenotypic switching has been demonstrated . Cell proliferation was detected with a cell counting kit-8 (CCK-8, Dojindo, Shanghai, China) after 48 h of culture at 37 °C.…”

“…25 In addition, the effect of Ang II on smooth muscle cell phenotypic switching has been demonstrated. 26 Cell proliferation was detected with a cell counting kit-8 (CCK-8, Dojindo, Shanghai, China) after 48 h of culture at 37 °C. Smooth muscle cells were treated with CCK-8 solution with a final concentration of 10% measured at 37 °C for 1−2 h, and then, microplate readers were used to measure absorbance at 450 nm.…”