AT1-receptor blockade, but not renin inhibition, reduces aneurysm growth and cardiac failure in fibulin-4 mice.

Journal of Hypertension
Luuk te RietJeroen Essers

Abstract

Increasing evidence supports a role for the angiotensin II-AT1-receptor axis in aneurysm development. Here, we studied whether counteracting this axis via stimulation of AT2 receptors is beneficial. Such stimulation occurs naturally during AT1-receptor blockade with losartan, but not during renin inhibition with aliskiren. Aneurysmal homozygous fibulin-4 mice, displaying a four-fold reduced fibulin-4 expression, were treated with placebo, losartan, aliskiren, or the β-blocker propranolol from day 35 to 100. Their phenotype includes cystic media degeneration, aortic regurgitation, left ventricular dilation, reduced ejection fraction, and fractional shortening. Although losartan and aliskiren reduced hemodynamic stress and increased renin similarly, only losartan increased survival. Propranolol had no effect. No drug rescued elastic fiber fragmentation in established aneurysms, although losartan did reduce aneurysm size. Losartan also increased ejection fraction, decreased LV diameter, and reduced cardiac pSmad2 signaling. None of these effects were seen with aliskiren or propranolol. Longitudinal micro-CT measurements, a novel method in which each mouse serves as its own control, revealed that losartan reduced LV growth more tha...Continue Reading

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Citations

Dec 7, 2016·Pharmacogenomics·Nicole K WilsonMibava Leducq Consortium
Jul 11, 2018·Hypertension·U Muscha Steckelings, Michael Bader
Jun 30, 2016·Journal of Hypertension·Masayuki TanemotoYu Ishimoto
Jun 30, 2016·Journal of Hypertension·Luuk Te RietJeroen Essers
Jan 8, 2019·The Journal of Clinical Investigation·Elena Gallo MacFarlaneHarry C Dietz

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Methods Mentioned

BETA
reverse transcription PCR
PCR
transgenic

Software Mentioned

Matlab
micro
CT Tools by Analyze
ATCODAS

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