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Publication
Mutation of the 5'-untranslated region stem-loop mRNA structure reduces type I
collagen deposition and arterial stiffness in male obese mice.
Authors Ramirez-Perez FI, Woodford ML, Morales-Quinones M, Grunewald ZI, Cabral-Amador
FJ, Yoshida T, Brenner DA, Manrique-Acevedo C, Martinez-Lemus LA, Chandrasekar
B, Padilla J
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal American journal of physiology. Heart and circulatory physiology
Year 2021
Date Published 8/1/2021
Volume : Pages 321 : H435 - H445
PubMed Reference 34242094
Abstract Arterial stiffening, a characteristic feature of obesity and type 2 diabetes,
contributes to the development and progression of cardiovascular diseases (CVD).
Currently, no effective prophylaxis or therapeutics is available to prevent or
treat arterial stiffening. A better understanding of the molecular mechanisms
underlying arterial stiffening is vital to identify newer targets and strategies
to reduce CVD burden. A major contributor to arterial stiffening is increased
collagen deposition. In the 5'-untranslated regions of mRNAs encoding for type I
collagen, an evolutionally conserved stem-loop (SL) structure plays an essential
role in its stability and post-transcriptional regulation. Here, we show that
feeding a high-fat/high-sucrose (HFHS) diet for 28?wk increases adiposity,
insulin resistance, and blood pressure in male wild-type littermates. Moreover,
arterial stiffness, assessed in vivo via aortic pulse wave velocity, and ex vivo
using atomic force microscopy in aortic explants or pressure myography in
isolated femoral and mesenteric arteries, was also increased in those mice.
Notably, all these indices of arterial stiffness, along with collagen type I
levels in the vasculature, were reduced in HFHS-fed mice harboring a mutation in
the 5'SL structure, relative to wild-type littermates. This protective vascular
phenotype in 5'SL-mutant mice did not associate with a reduction in insulin
resistance or blood pressure. These findings implicate the 5'SL structure as a
putative therapeutic target to prevent or reverse arterial stiffening and CVD
associated with obesity and type 2 diabetes.NEW & NOTEWORTHY In the
5'-untranslated (UTR) regions of mRNAs encoding for type I collagen, an
evolutionally conserved SL structure plays an essential role in its stability
and posttranscriptional regulation. We demonstrate that a mutation of the SL
mRNA structure in the 5'-UTR decreases collagen type I deposition and arterial
stiffness in obese mice. Targeting this evolutionarily conserved SL structure
may hold promise in the management of arterial stiffening and CVD associated
with obesity and type 2 diabetes.




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