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Suppressor of cytokine signaling 3 exerts divergent local vs systemic effects in angiotensin II‐induced endothelial dysfunction (1074.6)
Author(s) -
Li Ying,
Kinzenbaw Dale,
Modrick Marry,
Faraci Frank
Publication year - 2014
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.28.1_supplement.1074.6
Subject(s) - socs3 , angiotensin ii , vasodilation , endothelial dysfunction , medicine , endocrinology , acetylcholine , nitric oxide , cytokine , chemistry , receptor , pharmacology , cancer , suppressor
Angiotensin II (Ang II) plays a major role in vascular disease and hypertension, in part, through the interleukin‐6/STAT3 pathway. Pharmacological and genetic methods were used to investigate the role of SOCS3, a negative regulator of STAT3, in vascular disease. To examine direct effects of Ang II, we incubated carotid arteries for 22 hrs, then examined endothelial function using acetylcholine (Ach). Relaxation to Ach was similar in all arteries incubated with vehicle. A low concentration of Ang II (1 nmol/L) did not affect Ach‐induced vasodilation in wild‐type (WT) mice, but reduced that of SOCS3 haplodeficient (SOCS3 +/‐ ) mice by ~50% (P<0.05). This Ang II‐induced impairment was prevented by inhibitors of STAT3, IL‐6, NF‐κB, or a scavenger of superoxide. Responses to nitroprusside were similar in all groups. Ang II type 1 receptor (AT 1 R) mRNA levels were increased ~2 fold in SOCS3 +/‐ mice. In an in vivo model of Ang II‐dependent hypertension, systemic Ang II (1.4 mg/kg per day) infusion for 14 days reduced Ach‐induced vasodilation in both carotid and resistance arteries in brain from WT mice by ~60% (p<0.05). Surprisingly, deficiency in SOCS3 prevented the majority of Ang II‐induced endothelial dysfunction in both vessels, without affecting the pressor response to Ang II. These data suggest SOCS3 plays a divergent role in local versus systemic effects of Ang II on endothelial function. Grant Funding Source : supported by the NIH (HL‐62984, and HL‐113863), the Department of Veterans Affairs (BX001399), and t