Postnatal deficiency of ADAMTS1 ameliorates thoracic aortic aneurysm and dissection in mice

Abstract

Thoracic aortic aneurysm and dissection (TAAD), as a life-threatening cardiovascular disease, is characterized by extracellular matrix remodelling and an inflammatory response. A disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) is an inflammation-related protein that is able to degrade extracellular matrix proteins in arteries. Herein, we investigated whether ADAMTS1 contributes to the pathophysiology of TAAD in mice. Using the mouse model of β-aminopropionitrile (BAPN)-induced TAAD, we found that ADAMTS1 expression was upregulated beginning in the early stage of TAAD development and localized predominantly in the aortic adventitia. ADAMTS1-floxed mice and whole-body tamoxifen-inducible ADAMTS1 knockout mice (ADAMTS1 Ubc-Cre , ADAMTS1 KO) were generated to investigate the direct causal role of ADAMTS1 in TAAD development. The incidence and rupture rates of BAPN-induced TAAD in ADAMTS1 KO mice were significantly lower than those in ADAMTS1 mice (45.5 versus 81.8% and 18.2 versus 42.4%, respectively). Aortas from BAPN-treated ADAMTS1 mice displayed profound destruction of the elastic lamellae, abundant neutrophil and macrophage accumulation in the adventitia, obviously increased neutrophil proportions in peripheral blood and significantly increased expression of inflammatory factors in the early stage of TAAD induction, all of which were markedly suppressed in ADAMTS1 KO mice. Furthermore, ADAMTS1-deficient macrophages exhibited abrogated migration capacity both in vivo and in vitro. In conclusion, ADAMTS1 plays a crucial role in postnatal TAAD formation and rupture by regulating inflammatory responses, suggesting that ADAMTS1 might be a new therapeutic target for TAAD.

Angiotensin type 1 receptor regulates yes‑associated protein in vascular endothelial cells

“…of intimal tears. Multiple studies have combined AD and aortic aneurysm when studying disease mechanism (28,29); however, the results of the present study indicate that this may be inappropriate. Perhaps the two diseases share certain pathological mechanisms, but understanding the mechanism underlying intimal ruptures is key to elucidating the pathogenesis of AD.…”

β-Aminopropionitrile-induced aortic aneurysm and dissection in mice

“…Consequently, an estimated dose of 1 g/kg/d of BAPN is likely to be inaccurate. Therefore, it would be preferable to provide a more direct description of the BAPN dose, such as 1 to 3 mg/mL 42 , 45 , 46 or 0.2% to 0.6% [% wt/vol (2-6 mg/mL)] as reported in selected studies. 24 , 25 , 43 , 61 , 62 , 63 …”

“…In addition to the gelatinases, several studies have reported an increase in aortic MMP3. 50 , 57 , 45 A causal role in the changes of MMP abundance can be inferred from the single study in which suppression of MMP2 using short hairpin RNA attenuated BAPN-induced AAD formation. 53 Although multiple studies have shown the contribution of MMPs to the pathophysiology of BAPN-induced AAD, it remains unknown how BAPN alters aortic MMPs.…”

“…Ex vivo approaches have been used most frequently to evaluate BAPN-induced AAD in mice ( Fig 2 , C ). 12 , 47 , 48 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 63 , 64 , 79 BAPN induces heterogeneous aortic pathologies in the entire thoracic aorta. Because ex vivo approaches can detect AAD directly in any region, it has advantages for the evaluation of aortic pathologies in BAPN-administered mice.…”

ADAMTS Proteins and Vascular Remodeling in Aortic Aneurysms

“…Furthermore, Adamts1 -deficient mice had no inflammatory cell infiltration from inhibiting inflammatory cytokine levels and macrophage migration. Altogether, ADAMTS1 might be a suitable candidate as a potential therapeutic target for TAA [ 33 ].…”