Abstract
The mechanisms of cardiovascular protective effects of ghrelin and its synthetic analogs are still largely unknown. Our first aim was to ascertain whether or not natural and synthetic ligands of GHS-R1a are capable of interfering with the activity of the renin-angiotensin system. Second, since polymorphisms in the ACE gene have been associated with Alzheimer's dementia (AD) and ACE is potentially involved in brain β-amyloid degradation, we also investigated the state of ghrelin axis and inflammatory markers in patients with AD and vascular dementia (VaD). Desacyl ghrelin, hexarelin, EP80317, and GHRP-6 all significantly inhibited ACE activity in vitro; by comparison, the efficacies of ghrelin and MK-0677 were significantly lower, suggesting that ACE-inhibiting activity is unrelated to ligand affinity to GHS-R1a. ACE was capable of cleaving Aβ in vitro, reducing its ability to aggregate in fibrillar Aβ. Interestingly, this protective effect of ACE was blunted by enalapril but not hexarelin or EP80317. Desacyl ghrelin levels were lower in VaD subjects compared with AD and control subjects, whereas ghrelin and TNF-α levels were similar in all groups. VaD subjects demonstrated greater levels of mRNA for GHS-R1a, PPAR-γ and CD36 in peripheral blood lymphocytes compared with other groups. In conclusion, some GHSs are effective ACE-inhibitors, and this activity may contribute to their cardiovascular effects. Hexarelin or EP80317 do not inhibit the N-domain of ACE, which is also involved in the metabolism of β-amyloid, suggesting the possibility of developing new antihypertensive drugs with improved therapeutic potential.
| Original language | English |
|---|---|
| Pages (from-to) | 317-324 |
| Number of pages | 8 |
| Journal | Pharmacological Research |
| Volume | 66 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Oct 2012 |
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Keywords
- β-Amyloid
- ACE inhibitors
- Alzheimer's dementia
- EP80317
- Ghrelin
- Vascular dementia
ASJC Scopus subject areas
- Pharmacology
Cite this
Novel domain-selective ACE-inhibiting activity of synthetic growth hormone secretagogues. / Torsello, Antonio; Bresciani, Elena; Ravelli, Monica; Rizzi, Laura; Bulgarelli, Ilaria; Ricci, Giorgio; Ghiazza, Barbara; Del Puppo, Marina; Mainini, Veronica; Omeljaniuk, Robert J.; Tamiazzo, Laura; Mancia, Giuseppe; Magni, Fulvio; Locatelli, Vittorio.
In: Pharmacological Research, Vol. 66, No. 4, 10.2012, p. 317-324.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Novel domain-selective ACE-inhibiting activity of synthetic growth hormone secretagogues
AU - Torsello, Antonio
AU - Bresciani, Elena
AU - Ravelli, Monica
AU - Rizzi, Laura
AU - Bulgarelli, Ilaria
AU - Ricci, Giorgio
AU - Ghiazza, Barbara
AU - Del Puppo, Marina
AU - Mainini, Veronica
AU - Omeljaniuk, Robert J.
AU - Tamiazzo, Laura
AU - Mancia, Giuseppe
AU - Magni, Fulvio
AU - Locatelli, Vittorio
PY - 2012/10
Y1 - 2012/10
N2 - The mechanisms of cardiovascular protective effects of ghrelin and its synthetic analogs are still largely unknown. Our first aim was to ascertain whether or not natural and synthetic ligands of GHS-R1a are capable of interfering with the activity of the renin-angiotensin system. Second, since polymorphisms in the ACE gene have been associated with Alzheimer's dementia (AD) and ACE is potentially involved in brain β-amyloid degradation, we also investigated the state of ghrelin axis and inflammatory markers in patients with AD and vascular dementia (VaD). Desacyl ghrelin, hexarelin, EP80317, and GHRP-6 all significantly inhibited ACE activity in vitro; by comparison, the efficacies of ghrelin and MK-0677 were significantly lower, suggesting that ACE-inhibiting activity is unrelated to ligand affinity to GHS-R1a. ACE was capable of cleaving Aβ in vitro, reducing its ability to aggregate in fibrillar Aβ. Interestingly, this protective effect of ACE was blunted by enalapril but not hexarelin or EP80317. Desacyl ghrelin levels were lower in VaD subjects compared with AD and control subjects, whereas ghrelin and TNF-α levels were similar in all groups. VaD subjects demonstrated greater levels of mRNA for GHS-R1a, PPAR-γ and CD36 in peripheral blood lymphocytes compared with other groups. In conclusion, some GHSs are effective ACE-inhibitors, and this activity may contribute to their cardiovascular effects. Hexarelin or EP80317 do not inhibit the N-domain of ACE, which is also involved in the metabolism of β-amyloid, suggesting the possibility of developing new antihypertensive drugs with improved therapeutic potential.
AB - The mechanisms of cardiovascular protective effects of ghrelin and its synthetic analogs are still largely unknown. Our first aim was to ascertain whether or not natural and synthetic ligands of GHS-R1a are capable of interfering with the activity of the renin-angiotensin system. Second, since polymorphisms in the ACE gene have been associated with Alzheimer's dementia (AD) and ACE is potentially involved in brain β-amyloid degradation, we also investigated the state of ghrelin axis and inflammatory markers in patients with AD and vascular dementia (VaD). Desacyl ghrelin, hexarelin, EP80317, and GHRP-6 all significantly inhibited ACE activity in vitro; by comparison, the efficacies of ghrelin and MK-0677 were significantly lower, suggesting that ACE-inhibiting activity is unrelated to ligand affinity to GHS-R1a. ACE was capable of cleaving Aβ in vitro, reducing its ability to aggregate in fibrillar Aβ. Interestingly, this protective effect of ACE was blunted by enalapril but not hexarelin or EP80317. Desacyl ghrelin levels were lower in VaD subjects compared with AD and control subjects, whereas ghrelin and TNF-α levels were similar in all groups. VaD subjects demonstrated greater levels of mRNA for GHS-R1a, PPAR-γ and CD36 in peripheral blood lymphocytes compared with other groups. In conclusion, some GHSs are effective ACE-inhibitors, and this activity may contribute to their cardiovascular effects. Hexarelin or EP80317 do not inhibit the N-domain of ACE, which is also involved in the metabolism of β-amyloid, suggesting the possibility of developing new antihypertensive drugs with improved therapeutic potential.
KW - β-Amyloid
KW - ACE inhibitors
KW - Alzheimer's dementia
KW - EP80317
KW - Ghrelin
KW - Vascular dementia
UR - http://www.scopus.com/inward/record.url?scp=84864998047&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84864998047&partnerID=8YFLogxK
U2 - 10.1016/j.phrs.2012.06.006
DO - 10.1016/j.phrs.2012.06.006
M3 - Article
C2 - 22732396
AN - SCOPUS:84864998047
VL - 66
SP - 317
EP - 324
JO - Pharmacological Research
JF - Pharmacological Research
SN - 1043-6618
IS - 4
ER -