Submitted on May 6, 2009
Revised on June 3, 2009
Accepted on June 14, 2009
Treatment of Spontaneously Hypertensive Rats (SHR) with Rosiglitazone Ameliorates Cardiovascular Pathophysiology via Anti-oxidant Mechanisms in the Vasculature
Maria Assunta Potenza1, Sara Gagliardi2, Leonarda De Benedictis2, Addolorata Zigrino2, Edy Tiravanti1, Giuseppe Colantuono1, Antonio Federici2, Loredana Lorusso2, Vincenzo Benagiano2, Michael J. Quon3, and Monica Montagnani2*
1 University of Bari
2 University of Bari Medical School
3 NIH
* To whom correspondence should be addressed. E-mail: monica{at}farmacol.uniba.it.
Oxidative stress contributes to cardiovascular complications of diabetes, in part, by reducing bioavailability of nitric oxide (NO). We investigated mechanisms whereby the insulin sensitizer rosiglitazone may ameliorate oxidative stress in the vasculature of Spontaneously Hypertensive Rats (SHR). Nine-week old SHR were treated by gavage for 7 weeks with rosiglitazone (5 mg/kg/d) or vehicle control. Treatment of SHR with rosiglitazone lowered systolic blood pressure, reduced fasting plasma insulin and ADMA, and increased insulin sensitivity (when compared with vehicle-treatment). In vessel homogenates and serum from rosiglitazone-treated SHR, superoxide dismutase (SOD) activity was enhanced while 8-iso-PGF2a (lipid peroxidation product) was reduced (when compared with samples from vehicle-treated SHR). Moreover, expression of p22phox (catalytic subunit of NADPH oxidase) as well as nitrotyrosine and superoxide content were all reduced in aortas of rosiglitazone-treated SHR. In mesenteric vascular beds (MVB) isolated ex vivo from rosiglitazone-treated SHR, NO-dependent vasodilator actions of insulin were improved when compared with MVB from vehicle-treated SHR. Acute pre-treatment of MVB from vehicle-treated SHR with apocynin (NADPH oxidase inhibitor) enhanced vasodilator actions of insulin (results comparable to those in MVB from rosiglitazone-treated SHR). In Langendorff heart preparations from rosiglitazone-treated SHR, ischemia/reperfusion injury caused infarcts 40% smaller than in hearts from vehicle-treated SHR. Acute pre-treatment of hearts from vehicle-treated SHR with apocynin produced similar results. Finally, rosiglitazone treatment of endothelial cells in primary culture reduced superoxide induced by insulin resistant conditions. We conclude that rosiglitazone therapy in SHR increases SOD activity and decreases p22phox expression in the vasculature to reduce oxidant stress leading to an improved cardiovascular phenotype.
