Novel vasoactive intestinal peptide derivatives with improved stability protect rat alveolar L2 cells from cigarette smoke-induced cytotoxicity and apoptosis.
Vasoactive intestinal peptide (VIP) has been thought to be a promising candidate for asthma/chronic obstructive pulmonary disease (COPD), and our group previously developed several long-lasting VIP derivatives. The objective of the present study was to clarify the therapeutic potential of new VIP derivatives with improved chemical and metabolic stability. Exposure of rat alveolar L2 cells to cigarette smoke extract (CSE) for 1h led to release of lactate dehydrogenase (LDH) and decreased viability in a CSE concentration-dependent manner. There appeared to be marked induction of apoptosis after CSE exposure, as demonstrated by 59% elevation of caspase-3 activity and TUNEL staining. In contrast, a stabilized VIP derivative, [R(15,20,21), L(17)]-VIP-GRR (IK312532), at a concentration of 10(-7)M, exhibited 71% attenuation of LDH release and 85% decrease of the number of apoptotic cells. In addition to IK312532, new VIP derivatives also showed anti-apoptotic effects against CSE toxicity and marked reduction of nitric oxide production. In terms of cytoprotective effects, [R(15,20,21), L(17), A(24,25), des-N(28)]-VIP-GRR was more effective than VIP and IK312532, possibly due to the improved stability. Thus, the present study is the first to demonstrate that novel stabilized VIP derivatives exert anti-apoptotic and cytoprotective effects on CSE-induced cytotoxicity.
Department of Pharmacokinetics, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan.
Shingen
S
Misaka
Hideyuki
H
Sato
Yosuke
Y
Aoki
Takahiro
T
Mizumoto
Satomi
S
Onoue
Shizuo
S
Yamada
D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection; D003603:Cytotoxins / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D055550:Protein Stability; D011650:Pulmonary Alveoli / Q000166:cytology*; D051381:Rats; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000737:chemistry* / Q000633:toxicity; D014660:Vasoactive Intestinal Peptide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
D003603:Cytotoxins; D012906:Smoke; D009569:Nitric Oxide; D014660:Vasoactive Intestinal Peptide; D007770:L-Lactate Dehydrogenase; C505410:Casp3 protein, rat; D053148:Caspase 3; D053179:Caspase 7