TY - JOUR
T1 - Anti-hypertensive mechanisms of cyclic depsipeptide inhibitor ligands for G q/11 class G proteins
AU - Meleka, Matthew M.
AU - Edwards, Alethia J.
AU - Xia, Jingsheng
AU - Dahlen, Shelby A.
AU - Mohanty, Ipsita
AU - Medcalf, Matthew
AU - Aggarwal, Shaili
AU - Moeller, Kevin D.
AU - Mortensen, Ole V.
AU - Osei-Owusu, Patrick
N1 - Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/3
Y1 - 2019/3
N2 - Augmented vasoconstriction is a hallmark of hypertension and is mediated partly by hyper-stimulation of G protein couple receptors (GPCRs) and downstream signaling components. Although GPCR blockade is a key component of current anti-hypertensive strategies, whether hypertension is better managed by directly targeting G proteins has not been thoroughly investigated. Here, we tested whether inhibiting G q/11 proteins in vivo and ex vivo using natural cyclic depsipeptide, FR900359 (FR) from the ornamental plant, Ardisia crenata, and YM-254890 (YM) from Chromobacterium sp. QS3666, or it's synthetic analog, WU-07047 (WU), was sufficient to reverse hypertension in mice. All three inhibitors blocked G protein-dependent vasoconstriction, but to our surprise YM and WU and not FR inhibited K + -induced Ca 2+ transients and vasoconstriction of intact vessels. However, each inhibitor blocked whole-cell L-type Ca 2+ channel current in vascular smooth muscle cells. Subcutaneous injection of FR or YM (0.3 mg/kg, s.c.) in normotensive and hypertensive mice elicited bradycardia and marked blood pressure decrease, which was more severe and long lasting after the injection of FR relative to YM (FR t1/2 ≅ 12 h vs. YM t1/2 ≅ 4 h). In deoxycorticosterone acetate (DOCA)-salt hypertension mice, chronic injection of FR (0.3 mg/kg, s.c., daily for seven days) reversed hypertension (vehicle SBP: 149 ± 5 vs. FR SBP: 117 ± 7 mmHg), without any effect on heart rate. Our results together support the hypothesis that increased LTCC and G q/11 activity is involved in the pathogenesis of hypertension, and that dual targeting of both proteins can reverse hypertension and associated cardiovascular disorders.
AB - Augmented vasoconstriction is a hallmark of hypertension and is mediated partly by hyper-stimulation of G protein couple receptors (GPCRs) and downstream signaling components. Although GPCR blockade is a key component of current anti-hypertensive strategies, whether hypertension is better managed by directly targeting G proteins has not been thoroughly investigated. Here, we tested whether inhibiting G q/11 proteins in vivo and ex vivo using natural cyclic depsipeptide, FR900359 (FR) from the ornamental plant, Ardisia crenata, and YM-254890 (YM) from Chromobacterium sp. QS3666, or it's synthetic analog, WU-07047 (WU), was sufficient to reverse hypertension in mice. All three inhibitors blocked G protein-dependent vasoconstriction, but to our surprise YM and WU and not FR inhibited K + -induced Ca 2+ transients and vasoconstriction of intact vessels. However, each inhibitor blocked whole-cell L-type Ca 2+ channel current in vascular smooth muscle cells. Subcutaneous injection of FR or YM (0.3 mg/kg, s.c.) in normotensive and hypertensive mice elicited bradycardia and marked blood pressure decrease, which was more severe and long lasting after the injection of FR relative to YM (FR t1/2 ≅ 12 h vs. YM t1/2 ≅ 4 h). In deoxycorticosterone acetate (DOCA)-salt hypertension mice, chronic injection of FR (0.3 mg/kg, s.c., daily for seven days) reversed hypertension (vehicle SBP: 149 ± 5 vs. FR SBP: 117 ± 7 mmHg), without any effect on heart rate. Our results together support the hypothesis that increased LTCC and G q/11 activity is involved in the pathogenesis of hypertension, and that dual targeting of both proteins can reverse hypertension and associated cardiovascular disorders.
KW - Arginine vasopressin (CID: 644077)
KW - Bay K8644 (CID: 2303
KW - Blood pressure
KW - Calcium signaling
KW - Cyclic depsipeptides
KW - Endothelin-1 (CID: 16212950)
KW - FR900359 (CID: 14101198)
KW - G inhibitor ligands
KW - G proteins
KW - L-type calcium channel
KW - Nifedipine (CID: 63011)
KW - Phenylephrine (CID: 5284443)
KW - U46619 (CID: 5311493)
KW - WU-07047 (PMID: 25875152)
KW - YM-254890 (CID: 9919454)
UR - http://www.scopus.com/inward/record.url?scp=85059783341&partnerID=8YFLogxK
U2 - 10.1016/j.phrs.2019.01.012
DO - 10.1016/j.phrs.2019.01.012
M3 - Article
C2 - 30634050
AN - SCOPUS:85059783341
SN - 1043-6618
VL - 141
SP - 264
EP - 275
JO - Pharmacological Research
JF - Pharmacological Research
ER -