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Recoupling of eNOS with folic acid prevents abdominal aortic aneurysm formation in angiotensin II-infused apolipoprotein E mice.

Siu KL, Miao XN, Cai H - PLoS ONE (2014)

Bottom Line: This resulted in a reduction of AAA rate to 19.5%.This was accompanied by markedly improved tetrahydrobiopterin and nitric oxide bioavailability.Taken together, these data further establish a significant role of uncoupled eNOS in mediating AAA formation, and a universal efficacy of FA in preventing AAA formation via restoration of DHFR to restore eNOS function.

View Article: PubMed Central - PubMed

Affiliation: Divisions of Molecular Medicine and Cardiology, Departments of Anesthesiology and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.

ABSTRACT
We have previously shown that eNOS uncoupling mediates abdominal aortic aneurysm (AAA) formation in hph-1 mice. In the present study we examined whether recoupling of eNOS prevents AAA formation in a well-established model of Angiotensin II-infused apolipoprotein E (apoE) mice by targeting some common pathologies of AAA. Infusion of Ang II resulted in a 92% incidence rate of AAA in the apoE animals. In a separate group, animals were treated orally with folic acid (FA), which is known to recouple eNOS through augmentation of dihydrofolate reductase (DHFR) function. This resulted in a reduction of AAA rate to 19.5%. Imaging with ultrasound showed that FA markedly inhibited expansion of abdominal aorta. FA also abolished elastin breakdown and macrophage infiltration in the AAA animals. The eNOS uncoupling activity, assessed by L-NAME-sensitive superoxide production, was minimal at baseline but greatly exaggerated with Ang II infusion, which was completely attenuated by FA. This was accompanied by markedly improved tetrahydrobiopterin and nitric oxide bioavailability. Furthermore, the expression and activity of DHFR was decreased in Ang II-infused apoE mice specifically in the endothelial cells, while FA administration resulted in its recovery. Taken together, these data further establish a significant role of uncoupled eNOS in mediating AAA formation, and a universal efficacy of FA in preventing AAA formation via restoration of DHFR to restore eNOS function.

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Folic acid reduces inflammation in Ang II-infused apoE  mice.Abdominal aortas were collected from sham operated (left column), Ang II-infused (center column), and Ang II-infused and folic acid (FA, right column) treated apoE  mice 4 weeks after infusion. Tissues were then sectioned and stained for Mac-3 for infiltrating macrophage. Areas within the box were enlarged to better show details of the macrophage infiltration. The degree of macrophage infiltration was measured and quantified in Image J (*p<0.01 vs. all, n = 4 each).
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pone-0088899-g005: Folic acid reduces inflammation in Ang II-infused apoE mice.Abdominal aortas were collected from sham operated (left column), Ang II-infused (center column), and Ang II-infused and folic acid (FA, right column) treated apoE mice 4 weeks after infusion. Tissues were then sectioned and stained for Mac-3 for infiltrating macrophage. Areas within the box were enlarged to better show details of the macrophage infiltration. The degree of macrophage infiltration was measured and quantified in Image J (*p<0.01 vs. all, n = 4 each).

Mentions: To further analyze the extent of the vascular remodeling that occurred during AAA, we harvested and stained tissue sections of abdominal aortas. Representative images of H&E, VVG, and macrophage staining are shown in Figure 3, 4, and 5. Of note, Ang II infusion induced a marked adventitial hypertrophy (Figure 3). The representative picture also indicated a partially ruptured aneurysm. Furthermore, VVG staining reveals that the elastin fibers were flattened and broken in the Ang II-infused animals (Figure 4), implicating matrix degradation. Treatment with FA largely abolished these responses. Macrophage staining (Figure 5) shows that Ang II infusion significantly increased macrophage infiltration (n = 4 each), while FA treatment was able to attenuate this back to near baseline levels.


Recoupling of eNOS with folic acid prevents abdominal aortic aneurysm formation in angiotensin II-infused apolipoprotein E mice.

Siu KL, Miao XN, Cai H - PLoS ONE (2014)

Folic acid reduces inflammation in Ang II-infused apoE  mice.Abdominal aortas were collected from sham operated (left column), Ang II-infused (center column), and Ang II-infused and folic acid (FA, right column) treated apoE  mice 4 weeks after infusion. Tissues were then sectioned and stained for Mac-3 for infiltrating macrophage. Areas within the box were enlarged to better show details of the macrophage infiltration. The degree of macrophage infiltration was measured and quantified in Image J (*p<0.01 vs. all, n = 4 each).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928303&req=5

pone-0088899-g005: Folic acid reduces inflammation in Ang II-infused apoE mice.Abdominal aortas were collected from sham operated (left column), Ang II-infused (center column), and Ang II-infused and folic acid (FA, right column) treated apoE mice 4 weeks after infusion. Tissues were then sectioned and stained for Mac-3 for infiltrating macrophage. Areas within the box were enlarged to better show details of the macrophage infiltration. The degree of macrophage infiltration was measured and quantified in Image J (*p<0.01 vs. all, n = 4 each).
Mentions: To further analyze the extent of the vascular remodeling that occurred during AAA, we harvested and stained tissue sections of abdominal aortas. Representative images of H&E, VVG, and macrophage staining are shown in Figure 3, 4, and 5. Of note, Ang II infusion induced a marked adventitial hypertrophy (Figure 3). The representative picture also indicated a partially ruptured aneurysm. Furthermore, VVG staining reveals that the elastin fibers were flattened and broken in the Ang II-infused animals (Figure 4), implicating matrix degradation. Treatment with FA largely abolished these responses. Macrophage staining (Figure 5) shows that Ang II infusion significantly increased macrophage infiltration (n = 4 each), while FA treatment was able to attenuate this back to near baseline levels.

Bottom Line: This resulted in a reduction of AAA rate to 19.5%.This was accompanied by markedly improved tetrahydrobiopterin and nitric oxide bioavailability.Taken together, these data further establish a significant role of uncoupled eNOS in mediating AAA formation, and a universal efficacy of FA in preventing AAA formation via restoration of DHFR to restore eNOS function.

View Article: PubMed Central - PubMed

Affiliation: Divisions of Molecular Medicine and Cardiology, Departments of Anesthesiology and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.

ABSTRACT
We have previously shown that eNOS uncoupling mediates abdominal aortic aneurysm (AAA) formation in hph-1 mice. In the present study we examined whether recoupling of eNOS prevents AAA formation in a well-established model of Angiotensin II-infused apolipoprotein E (apoE) mice by targeting some common pathologies of AAA. Infusion of Ang II resulted in a 92% incidence rate of AAA in the apoE animals. In a separate group, animals were treated orally with folic acid (FA), which is known to recouple eNOS through augmentation of dihydrofolate reductase (DHFR) function. This resulted in a reduction of AAA rate to 19.5%. Imaging with ultrasound showed that FA markedly inhibited expansion of abdominal aorta. FA also abolished elastin breakdown and macrophage infiltration in the AAA animals. The eNOS uncoupling activity, assessed by L-NAME-sensitive superoxide production, was minimal at baseline but greatly exaggerated with Ang II infusion, which was completely attenuated by FA. This was accompanied by markedly improved tetrahydrobiopterin and nitric oxide bioavailability. Furthermore, the expression and activity of DHFR was decreased in Ang II-infused apoE mice specifically in the endothelial cells, while FA administration resulted in its recovery. Taken together, these data further establish a significant role of uncoupled eNOS in mediating AAA formation, and a universal efficacy of FA in preventing AAA formation via restoration of DHFR to restore eNOS function.

Show MeSH
Related in: MedlinePlus