Valproic acid prevents hemorrhage-associated lethality and affects the acetylation pattern of cardiac histones.
Pharmacological inhibitors of histone deacetylases (HDAC) demonstrate cytoprotective effects both in vitro and in vivo. In this study, we investigated whether valproic acid (VPA), a known mood stabilizer and anticonvulsant with HDAC-inhibiting activity, improves survival following otherwise lethal hemorrhage in rats. We found that preinsult injection of VPA (300 mg/kg, twice) prolonged the survival of severely hypotensive animals up to 5 times. VPA treatment increased the acetylation of nonhistone and histone proteins in the rat heart. The pattern of modifications of individual histones revealed hyperacetylation of histones H2A, H3, and H4, indicating the presence of active genes. Expression of HSP70 and superoxide dismutase, implicated in the modulation of vitality, was increased by VPA. Our results reveal that VPA offers considerable protection in the hemorrhagic shock model and suggest a role for HDAC inhibition in mediating VPA actions.
Gonzales
Earl
E
Department of Surgery, Trauma Research and Readiness Institute for Surgery, Uniformed Services University of the Health Sciences, Bethesda, , MD 20814, USA.
Chen
Huazhen
H
Munuve
Richard
R
Mehrani
Tina
T
Britten-Webb
Joy
J
Nadel
Amal
A
Alam
Hasan B
HB
Wherry
David
D
Burris
David
D
Koustova
Elena
E