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Methionine Sulfoxide Reductase‐A Deficient Mice Exhibit Sympathetic Activity‐Dependent Oxidative Stress: Implications for End‐Organ Damage
Author(s) -
Sabharwal Rasna,
Abboud Francois M.,
Chapleau Mark W.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1237.2
Subject(s) - msra , oxidative stress , endocrinology , medicine , angiotensin ii , methionine , aorta , chemistry , ascending aorta , biochemistry , receptor , amino acid
Methionine sulfoxide reductase A (MsrA) selectively reverses oxidation of protein methionine and protects against oxidative damage. We recently reported that MsrA deficient (−/−) mice exhibit increased sympathetic tone under basal conditions, and augmented angiotensin II (Ang II) hypertension associated with left ventricular (LV) dysfunction and dilatation of ascending aorta; with the Ang II‐related pathologies abrogated by treatment with the sympathoinhibitory drug rilmenidine (RIL) [FASEB J, 2015; Auton Neurosci, 2015]. The aims of this study were to determine if MsrA−/− mice exhibit oxidative stress in LV and ascending aorta, and if basal and Ang II‐induced oxidative stress are dependent on sympathetic activity. Superoxide (O 2 •− ) was measured in tissue sections from LV and ascending aorta (dihydroethidium staining) from untreated control C57BL6 and MsrA−/− mice (12–16 wks of age), and mice infused with Ang II (1000 ng/kg/min, SC) with or without ICV infusion of RIL over the last two weeks of Ang II infusion. O 2 •− levels in LV and aorta were significantly higher in MsrA−/− (n=8) vs. C57BL6 (n=7) mice, both under basal conditions (untreated) and after 4 weeks of Ang II infusion (Table). Ang II‐induced increases in O 2 •− were much greater in MsrA−/− mice (Table). Treatment of Ang II‐infused mice with RIL normalized O 2 •− levels in both genotypes (Table). Furthermore, O 2 •− levels in Ang II‐infused mice (n=7) were positively correlated with sympathetic tone measured in the same mice (r 2 = 0.76 for LV, r 2 = 0.88 for ascending aorta, P<0.05). In summary: (1) oxidative stress is evident in LV and ascending aorta of MsrA−/− mice under basal condition, (2) MsrA−/− and Ang II infusion synergistically increase oxidative stress, and (3) oxidative stress during chronic Ang II infusion is entirely dependent on sympathetic activity. Taken together, our results suggest that sympathetic activity‐dependent oxidative stress contributes to LV dysfunction/remodeling and aortic dilatation in MsrA−/− mice. Support or Funding Information HL14388, VA