Key result
Eplerenone outperforms amiloride in preventing aortic aneurysms and prolonging lifespan in Tgfb1 L/L mice.
Why the study?
Loss-of-function mutations in TGF-β signaling genes cause proximal aortic aneurysms in humans with Loeys-Dietz Syndrome, and mice homozygous for the loss-of-function mutation in the Tgfb1 gene develop proximal aortic aneurysms associated with elevated plasma aldosterone levels.
Does chronic oral administration of eplerenone prevent proximal aortic aneurysms and elongate lifespan in Tgfb1 L/L mice?
Does chronic oral administration of eplerenone prevent proximal aortic aneurysms and elongate lifespan in Tgfb1 L/L mice?
Mineralocorticoid receptor blockade with eplerenone prevents proximal aortic aneurysms, restores aortic collagen and elastin crosslinks, and prolongs survival in a mouse model of TGF-β1 deficiency, suggesting potential utility in Loeys-Dietz Syndrome.
Answers are grounded in this paper and cite their sources.
Should not yet change Loeys-Dietz syndrome management; leaves open whether mineralocorticoid receptor antagonism prevents aortic aneurysms in human clinical trials.
Loss-of-function mutations in the component genes of transforming growth factor (TGF)-β signaling have been demonstrated to cause proximal aortic aneurysms in humans (Loeys-Dietz Syndrome). Recently, we have demonstrated that homozygous mice for the loss-of-mutation mutation in the Tgfb1 gene ( Tgfb1 L/L mice) develop proximal aortic aneurysms which is associated with elevated plasma aldosterone levels. Here we found that chronic oral administration of a mineralocorticoid receptor antagonist eplerenone substantially prevented aortic aneurysms and elongated lifespans in Tgfb1 L/L mice. Amiloride, which caused depressor effects comparative to eplerenone, resulted in less protection against aneurysms and early deaths than eplerenone in Tgfb1 L/L mice. The reduced aortic levels of pyridinoline and (iso)desmosine which are collagen and elastin stable crosslinks, and of the expression of their associated enzymes in Tgfb1 L/L mice were significantly restored by the eplerenone administration. These results suggest that mineralocorticoid receptor blockade is useful to prevent aortic aneurysms and early deaths in Loeys-Dietz Syndrome. (150 words)
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Kakoki et al. (2026) studied Proximal aortic aneurysms (Loeys-Dietz Syndrome model). Eplerenone vs. Amiloride or untreated control was evaluated on Prevention of aortic aneurysms and lifespan elongation. Chronic oral eplerenone substantially prevented aortic aneurysms, elongated lifespans, and restored aortic collagen/elastin crosslinks in Tgfb1 L/L mice more effectively than amiloride.
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