RECS1 is a Negative Regulator of Matrix Metalloproteinase-9 Production and Aged RECS1 Knockout Mice are Prone to Aortic Dilation

Abstract

RECS1 is a mechanical stress responsive gene and RECS1 knockout (KO) mice (older than 14 months) are prone to cystic medial degeneration (CMD). The present study was designed to assess whether RECS1 KO mice have altered gelatinase (matrix metalloproteinase (MMP)-2 and MMP-9) levels and whether they are prone to aortic dilation. Aortic and plasma gelatinase levels in RECS1 KO and wild-type (WT) mice were assessed by gelatin zymography and Western blot analysis. Pro-MMP-9 (in the aorta), neutrophil gelatinase-associated lipocalin/MMP-9 complex (NGAL-MMP-9, in plasma), and active-MMP-9 protein levels were more abundant in KO mice throughout adulthood compared with WT mice. Aortic MMP-2, aortic MMP-9, and plasma MMP-9 activation increased with age, even though the aortic pro-MMP-9, plasma NGAL-MMP-9, aortic and plasma pro-MMP-2 production decreased: this was true both for the WT and KO animals. Aortic pro-MMP-2, aortic active-MMP-2, and plasma pro-MMP-2 protein levels were higher in the aged KO mice, but they were lower in the young KO mice than those in WT mice. Thoracic aortic dilation was observed only in the aged KO mice. In situ zymographic experiments confirmed that the increased aortic gelatinase activities were associated with CMD and aortic dilation observed in the aged KO mice. RECS1 negatively regulates aortic MMP-9 production and knocking out RECS1 induces susceptibility to aortic dilation as well as CMD in the aged mice. The present study suggests that RECS1 plays protective roles in vascular remodeling. We speculate that inhibiting unfavorable deposition and extracellular matrix degradation are both important for prevention and treatment of aneurysms.