HDAC inhibition attenuates inflammatory, hypertrophic, and hypertensive responses in spontaneously hypertensive rats.
Reactive oxygen species and proinflammatory cytokines contribute to cardiovascular diseases. Inhibition of downstream transcription factors and gene modifiers of these components are key mediators of hypertensive response. Histone acetylases/deacetylases can modulate the gene expression of these hypertrophic and hypertensive components. Therefore, we hypothesized that long-term inhibition of histone deacetylase with valproic acid might attenuate hypertrophic and hypertensive responses by modulating reactive oxygen species and proinflammatory cytokines in SHR rats. Seven-week-old SHR and WKY rats were used in this study. Following baseline blood pressure measurement, rats were administered valproic acid in drinking water (0.71% wt/vol) or vehicle, with pressure measured weekly thereafter. Another set of rats were treated with hydralazine (25 mg/kg per day orally) to determine the pressure-independent effects of HDAC inhibition on hypertension. Following 20 weeks of treatment, heart function was measured using echocardiography, rats were euthanized, and heart tissue was collected for measurement of total reactive oxygen species, as well as proinflammatory cytokine, cardiac hypertrophic, and oxidative stress gene and protein expressions. Blood pressure, proinflammatory cytokines, hypertrophic markers, and reactive oxygen species were increased in SHR versus WKY rats. These changes were decreased in valproic acid-treated SHR rats, whereas hydralazine treatment only reduced blood pressure. These data indicate that long-term histone deacetylase inhibition, independent of the blood pressure response, reduces hypertrophic, proinflammatory, and hypertensive responses by decreasing reactive oxygen species and angiotensin II type1 receptor expression in the heart, demonstrating the importance of uncontrolled histone deacetylase activity in hypertension.
Cardinale
Jeffrey P
JP
Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA.
Sriramula
Srinivas
S
Pariaut
Romain
R
Guggilam
Anuradha
A
Mariappan
Nithya
N
Elks
Carrie M
CM
Francis
Joseph
J
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D006332:Cardiomegaly / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004452:Echocardiography; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
D000959:Antihypertensive Agents; D056572:Histone Deacetylase Inhibitors; D006830:Hydralazine; D014635:Valproic Acid; D006655:Histone Deacetylases