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.