Enzymatic degradation of
elastin by
matrix metalloproteinases (
MMPs) leads to the permanent dilation of aortic wall and constitutes the most prominent characters of
aortic aneurysm and aging-related medial degeneration.
Hydrogen sulfide (H2S) as a
gasotransmitter exhibits a wide variety of cardio-protective functions through its anti-inflammatory and anti-oxidative actions.
Cystathionine gamma-lyase (CSE) is a main H2S-generating
enzyme in cardiovascular system. The regulatory roles of CSE/H2S system on
elastin homeostasis and blood vessel degeneration have not yet been explored. Here we found that aged CSE knockout mice had severe aortic dilation and elastic degradation in abdominal aorta and were more sensitive to
angiotensin II-induced aortic elastolysis and medial degeneration. Administration of
NaHS would protect the mice from
angiotensin II-induced
inflammation, gelatinolytic activity,
elastin fragmentation, and aortic dilation. In addition, human
aortic aneurysm samples had higher inflammatory infiltration and lower expression of CSE. In cultured smooth muscle cells (SMCs), TNFα-induced MMP2/9 hyperactivity and elastolysis could be attenuated by exogenously applied
NaHS or CSE overexpression while further deteriorated by complete knockout of CSE. It was further found that H2S inhibited MMP2 transcription by posttranslational modification of Sp1 via S-sulfhydration. H2S also directly suppressed
MMP hyperactivity by S-sulfhydrating the
cysteine switch motif. Taken together, this study revealed the involvement of CSE/H2S system in the pathogenesis of aortic elastolysis and medial degeneration by maintaining the inactive form of
MMPs, suggesting that CSE/H2S system can be a target for the prevention of age-related medial degeneration and treatment of
aortic aneurysm.