Cardioprotective effect of endogenous pituitary adenylate cyclase-activating polypeptide on Doxorubicin-induced cardiomyopathy in mice.
BACKGROUND
Pituitary adenylate cyclase-activating polypeptide (PACAP) is known as a cytoprotective polypeptide. PACAP and its receptors are expressed in the heart, but it is unclear whether PACAP exerts its protective effect on the myocardium in vivo. The aim of the present study was to investigate whether endogenous PACAP has a cardioprotective effect on Doxorubicin (Dox)-induced cardiomyopathy.


RESULTS
Dox was intraperitoneally injected to induce cardiomyopathy in wild type (WT) and PACAP knockout (ie, PACAP+/- and PACAP-/-) mice. The survival rates up to 15 days of PACAP+/- mice and PACAP-/- mice were significantly less than that of WT mice. Cardiac function, measured by echocardiography, was significantly lower in PACAP+/- mice than in WT mice at day 10. Morphological examination of sections of myocardium showed degenerative change and fibrosis in PACAP+/- mice at day 10. Serum reactive oxygen metabolites (a marker of oxidative stress), the number of 8-hydroxy-deoxyguanosine-positive nuclei and TdT-mediated dUTP nick end-labeling (TUNEL) positive nuclei in the myocardium were higher in PACAP+/- mice than WT mice. However, continuous subcutaneous administration of PACAP38 was able to prevent the myocardial damage typically caused by Dox injection in PACAP+/-.


CONCLUSIONS
These results suggest that endogenous PACAP might attenuate Dox-induced myocardial damage and that its mechanism of action is likely to be associated with the reduction of oxidative stress and mediated via anti-apoptotic effects.
Mori
Hiroyoshi
H
Division of Cardiology, Department of Internal Medicine, Showa University Fujigaoka Hospital, Yokohama, Japan.
Nakamachi
Tomoya
T
Ohtaki
Hirokazu
H
Yofu
Sachiko
S
Sato
Atsushi
A
Endo
Kimi
K
Iso
Yoshitaka
Y
Suzuki
Hiroshi
H
Takeyama
Youichi
Y
Shintani
Norihito
N
Hashimoto
Hitoshi
H
Baba
Akemichi
A
Shioda
Seiji
S
D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000139:chemically induced / Q000401:mortality / Q000473:pathology*; D002316:Cardiotonic Agents; D004317:Doxorubicin / Q000633:toxicity*; D004562:Electrocardiography; D005355:Fibrosis; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000172:deficiency / Q000502:physiology*; D015996:Survival Rate
D002316:Cardiotonic Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D004317:Doxorubicin