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Leptin Increases Blood Pressure Acting via Transient Receptor Potential (TRP) Channels in the Carotid Body
Author(s) -
Shin Mi Kyung,
Hwang Min Woo,
Yeung Bonnie Hoyee,
Shirahata Machiko,
Tang Winnie Wanyee,
Sham James S.K.,
Polotsky Vsevolod Y
Publication year - 2017
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.31.1_supplement.1025.2
Subject(s) - leptin , leptin receptor , medicine , endocrinology , blood pressure , transient receptor potential channel , carotid body , receptor , obesity , carotid arteries
Rationale Obesity leads to cardiovascular morbidity and mortality acting via multiple mechanisms including hypertension and obstructive sleep apnea. Obesity leads to high levels of adipokine leptin. Increased leptin levels have been previously reported in sleep apnea and implicated in increased sympathetic activity and the pathogenesis of hypertension. However, mechanisms of the effects of leptin on blood pressure are unclear. The carotid bodies (CB) express leptin receptor (LepR), but the mechanisms and consequences of leptin action in CB are unknown. We have previously demonstrated that leptin enhances carotid sinus nerve activity in response to hypoxia and this effect is abolished by non‐selective blockers of transient receptor potential (TRP) channels (Shirahata et al., 2015). We hypothesized that high levels of circulating leptin signal via LepR in CB leading to hypertension and that leptin's effect is mediated via TRP channels. Methods 1) Male C57BL/6J mice (n=6) were implanted with telemetry in the left femoral artery for blood pressure monitoring at baseline, during leptin infusion (120ug/day for 3 days via a SC pump) before and after CB denervation; 2) LepR deficient db/db mice were implanted with telemetry; blood pressure measurements were performed followed by infection with adenovirus carrying the LepR gene ( Ad‐LepR, n=5) or luciferase (control, Ad‐Luc, n=5) followed by BP measurements; 3) Expression of different TRP channels was measured in CB of wildype C57BL/6J, leptin deficient ob/ob mice and LepR deficient db/db mice; 4) TRP channel expression was measured in db/db mice infected with Ad‐LepR vs Ad‐Luc ; 5) blood pressure monitoring was performed in male C57BL/6J mice (n= 9) at baseline, during leptin infusion with or without Trpm7 inhibitor, FTY720 (10mg/kg, sc, n=3) for 24 hrs. Results 1) In mice with intact CB, leptin increased mean arterial pressure by 13 mm Hg during the day and by 16 mm Hg at night ( p = 0.003 for the effect of leptin). CB denervation completely abolished leptin‐induced hypertension ( p < 0.001). 2) wildtype C57BL/6J mice showed significantly higher CB expression of Trpm7 compared to ob/ob and db/db mice; 3) LepR expression in CB of db/db mice dramatically increased Trpm7 expression; 4) Trpm7 inhibitor FTY720 abolished leptin‐induced hypertension. Conclusions Leptin increases blood pressure by acting via LepR and downstream Trpm7 channels in the CB. Support or Funding Information HL133100, HL128970