Aging, matrix metalloproteinase imaging, and survival prospects in aortic aneurysm
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Abstract
Age is a risk factor for aortic aneurysm (AA), and different segments of the aorta exhibit varying susceptibilities to aneurysm. The specific factors that contribute to the higher incidence of AA and its complications with aging remain unclear. Matrix metalloproteinases (MMPs) are elevated in AA. However, the connection between aging, aortic MMP activity, and the increased prevalence of AA and its complications has not been systematically evaluated. This study leveraged MMP-targeted molecular imaging to investigate how aging affects aortic MMP expression and activity, as well as aneurysm development and survival. Methods: AA development and animal survival were monitored for 28 days after Angiotensin (Ang)-II infusion in 8-10-week-old (young) and >51-week-old (old) Apoe-/- mice. Aortic MMP activation was quantified by PET/CT using an MMP-targeted tracer, 64Cu-RYM2, at baseline and 1 week after Ang II infusion. MMP activity and expression were quantified by tissue zymography and quantitative reverse transcription polymerase chain reaction, and compared between different segments of the aorta in young and old animals, and before and after Ang II infusion. Results: Old animal survival to 28 days was significantly lower than that of young Ang-II-infused Apoe-/- mice (P < 0.05). 64Cu-RYM2 PET/CT showed significantly higher aortic MMP activation before and 1 week after Ang-II infusion in old compared to young Apoe-/- mice. The 64Cu-RYM2 signal was significantly higher in animals that did not survive 28 days than those that did (P < 0.01). MMP activity significantly increased by 4 days after Ang-II infusion, when dissection was found in a subset of Apoe-/- mice; and was significantly higher in the dissected, compared to adjacent, apparently normal, segments of the aorta. MMP activity was also significantly higher in the ascending thoracic aorta of untreated young and old mice, as well as of Ang-II-treated Apoe-/- mice (which was associated with significantly higher Mmp2 gene expression), and of old wild-type mice. Conclusion: Aging is associated with increased MMP activity along the aorta and worse AA survival. MMP-targeted molecular imaging can inform the aneurysm survival prospects. Selective MMP inhibitors and tracers may help prevent and track aneurysm growth, dissection, and rupture.
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Abstract
Age is a risk factor for aortic aneurysm (AA), and different segments of the aorta exhibit varying susceptibilities to aneurysm. The specific factors that contribute to the higher incidence of AA and its complications with aging remain unclear. Matrix metalloproteinases (MMPs) are elevated in AA. However, the connection between aging, aortic MMP activity, and the increased prevalence of AA and its complications has not been systematically evaluated. This study leveraged MMP-targeted molecular imaging to investigate how aging affects aortic MMP expression and activity, as well as aneurysm development and survival.
Methods
AA development and animal survival were monitored for 28 days after Angiotensin (Ang)-II infusion in 8-10-week-old (young) and >51-week-old (old) Apoe−/− mice. Aortic MMP activation was quantified by PET/CT using an MMP-targeted tracer, 64Cu-RYM2, at baseline and 1 week after Ang II infusion. MMP activity and expression were quantified by tissue zymography and quantitative reverse transcription polymerase chain reaction, and compared between different segments of the aorta in young and old animals, and before and after Ang II infusion.
Results
Old animals’ survival to 28 days was significantly lower than that of young Ang-II-infused Apoe−/− mice (P < 0.05). 64Cu-RYM2 PET/CT showed significantly higher aortic MMP activation before and 1 week after Ang-II infusion in old compared to young Apoe−/−mice. The 64Cu-RYM2 signal was significantly higher in animals that did not survive 28 days than those that did (P < 0.01). MMP activity significantly increased by 4 days after Ang-II infusion, when dissection was found in a subset of Apoe−/− mice; and was significantly higher in the dissected, compared to adjacent, apparently normal, segments of the aorta. MMP activity was also significantly higher in the ascending thoracic aorta of untreated young and old mice, as well as of Ang-II-treated Apoe−/−mice (which was associated with significantly higher Mmp2 gene expression), and of old wild-type mice.
Conclusion
Aging is associated with increased MMP activity along the aorta and worse AA survival. MMP-targeted molecular imaging can inform the aneurysm survival prospects. Selective MMP inhibitors and tracers may help prevent and track aneurysm growth, dissection, and rupture.
Competing Interest Statement
JT and MMS are inventors on a Yale University patent entitled Matrix Metalloproteinase Inhibitors and Imaging Agents, And Methods Using Same (US20200283428A1, WO2017177144A1). MMS spouse is an employee of Boehringer Ingelheim. The other authors report no conflicts.
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- last seen: 2026-05-20T01:45:00.602351+00:00