Long-acting analogue of vasoactive intestinal peptide, [R15, 20, 21, L17]-VIP-GRR (IK312532), protects rat alveolar L2 cells from the cytotoxicity of cigarette smoke.

Abstract

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) act as neurotransmitters in numerous biological responses. We previously reported that the replacement of Lys by Arg, and Met by Leu in VIP (IK312532; [Arg15, 20, 21, Leu17]-VIP) resulted in a significant improvement in metabolic stability and biological activity. In the present study, we investigated the effect of VIP and its related peptides including long-acting VIP derivative (IK312532) and PACAP27 on the cytotoxicity of cigarette smoke extract (CSE), a causative factor of chronic obstructive pulmonary disease (COPD), in rat alveolar L2 cells. RT-PCR displayed the dominant expression of mRNA for the VIP-specific VPAC2 receptor in L2 cells, and VIP and the related peptides showed the specific binding activity and potent stimulation of adenylate cyclase. CSE at a concentration of 0.1% or higher induced significant apoptotic death of L2 cells. Interestingly, the addition of neuropeptides at a concentration of 10(-11) M or higher in L2 cells with CSE (0.25%) resulted in significant attenuation of cell death with the deactivation of CSE-evoked caspase-3 activity. IK312532 was much stable against the enzymatic digestion compared to VIP, and the protective effect of IK312532 was 1.6-fold higher than that of VIP. Taken together with our previous report showing that IK312532 has long-acting relaxant activity in the lung, IK312532 may be a potential candidate for drug treatment of asthma and COPD.

• Authors: Satomi Onoue, Kosuke Endo, Yuki Ohmori, Shizuo Yamada, Ryohei Kimura, Takehiko Yajima, Kazuhisa Kashimoto
• Journal: Regulatory peptides (Regul Pept) Vol. 123 Issue 1-3 Pg. 193-9 (Dec 15 2004) ISSN: 0167-0115 [Print] Netherlands
• PMID: 15518912 (Publication Type: Journal Article)

Chemical References

• ADCYAP1 protein, human
• Adcyap1 protein, rat
• DNA, Complementary
• Nerve Growth Factors
• Neuropeptides
• Neurotransmitter Agents
• Pituitary Adenylate Cyclase-Activating Polypeptide
• RNA, Messenger
• Receptors, Vasoactive Intestinal Peptide
• Receptors, Vasoactive Intestinal Peptide, Type II
• Receptors, Vasoactive Intestinal Polypeptide, Type I
• Smoke
• Vasoactive Intestinal Peptide
• CASP3 protein, human
• Casp3 protein, rat
• Caspase 3
• Caspases

Topics

• Animals
• Asthma (drug therapy)
• Base Sequence
• Bronchoalveolar Lavage Fluid (chemistry)
• Caspase 3
• Caspases (metabolism)
• Cell Death (drug effects)
• Cell Line
• DNA, Complementary (genetics)
• Gene Expression (drug effects)
• Humans
• Nerve Growth Factors (pharmacology)
• Neuropeptides (pharmacology)
• Neurotransmitter Agents (pharmacology)
• Pituitary Adenylate Cyclase-Activating Polypeptide
• Pulmonary Alveoli (cytology, drug effects, metabolism)
• Pulmonary Disease, Chronic Obstructive (drug therapy)
• RNA, Messenger (genetics, metabolism)
• Rats
• Receptors, Vasoactive Intestinal Peptide (genetics)
• Receptors, Vasoactive Intestinal Peptide, Type II
• Receptors, Vasoactive Intestinal Polypeptide, Type I
• Smoke (adverse effects)
• Tobacco
• Vasoactive Intestinal Peptide (chemistry, pharmacology)