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PRECLINICAL STUDY

Serofendic Acid, a Novel Substance Extracted From Fetal Calf Serum, Protects Against Oxidative Stress in Neonatal Rat Cardiac Myocytes

Toshihiro Takeda, MD^_*, Masaharu Akao, MD, PhD^_*,_*, Madoka Matsumoto-Ida, MD^_*, Masashi Kato, MD^_*, Hiroyuki Takenaka, MD^_*, Yasuki Kihara, MD, PhD^_*, Toshiaki Kume, PhD, Akinori Akaike, PhD and Toru Kita, MD, PhD^_*

^_* Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
Department of Pharmaceutical Science, Kyoto University Graduate School of Pharmacology, Kyoto, Japan.

Manuscript received June 19, 2005; revised manuscript received December 14, 2005, accepted December 19, 2005.

^_* Reprint requests and correspondence: Dr. Masaharu Akao, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. (Email: akao{at}kuhp.kyoto-u.ac.jp).

OBJECTIVES: We examined whether serofendic acid (SFA) has protective effects against oxidative stress in cardiac myocytes.

BACKGROUND: We previously identified a novel endogenous substance, SFA, from a lipophilic extract of fetal calf serum. Serofendic acid protects cultured neurons against the cytotoxicity of glutamate, nitric oxide, and oxidative stress.

METHODS: Primary cultures of neonatal rat cardiac myocytes were exposed to oxidative stress (H₂O₂, 100 µmol/l) to induce cell death. Effects of SFA were evaluated with a number of markers of cell death.

RESULTS: Pretreatment with SFA (100 µmol/l) significantly suppressed markers of cell death, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining and cell viability assay. Loss of mitochondrial membrane potential (_m) is a critical step of the death pathway, which is triggered by matrix calcium overload and reactive oxygen species. Serofendic acid prevented the _m loss induced by H₂O₂ in a concentration-dependent manner (with saturation by 100 µmol/l). Serofendic acid remarkably suppressed the H₂O₂-induced matrix calcium overload and intracellular accumulation of reactive oxygen species. The protective effect of SFA was comparable to that of a mitochondrial adenosine triphosphate-sensitive potassium (mitoK_ATP) channel opener, diazoxide. Furthermore, mitoK_ATP channel blocker, 5-hydroxydecanoate (500 µmol/l), abolished the protective effect of SFA. Co-application of SFA (100 µmol/l) and diazoxide (100 µmol/l) did not show an additive effect. Thus, SFA inhibited the oxidant-induced mitochondrial death pathway, presumably through activation of the mitoK_ATP channel.

CONCLUSIONS: Serofendic acid protects cardiac myocytes against oxidant-induced cell death by preserving the functional integrity of mitochondria.

Abbreviations and Acronyms   5-HD = 5-hydroxydecanoate   m = mitochondrial membrane potential   [Ca2+]m = mitochondrial matrix calcium   DAPI = 4’,6-diamidino-2-phenylindole   DCF = chloromethyl-2,7-dichlorodihydrofluorescein diacetate   DMEM = Dulbecco’s Modified Eagle Medium   FACS = fluorescence-activated cell sorter   MitoKATP = mitochondrial adenosine triphosphate-sensitive potassium   MPTP = mitochondrial permeability transition pore   ROS = reactive oxygen species   SFA = serofendic acid   TMRE = tetramethylrhodamine ethyl ester   TUNEL = terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling

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