Author + information
- Li Ming,
- Nawazish Naqvi,
- Eiji Yahiro,
- Eddie W. Bradley,
- Louis J. Dell'Italia and
- Ahsan Husain
Angiotensin II (Ang II) simultaneously stimulates two counteracting receptors, Ang II type 1 and type 2 receptors (AT1R and AT2R). AT2R is up-regulated and has protective roles in advanced atherosclerotic lesions in apolipoprotein E-deficient (apoE(-/-)) mice. The present study is to investigate the cardiovascular role of AT2R at the onset of atherosclerosis in young apoE(-/-) mice.
Nine-week-old male C57BL/6 and apoE(-/-) mice were used. ApoE(-/-) and C57BL/6 mice were fed a low fat cholesterol diet (10% kcal from fat, 0% cholesterol). Vehicle, Ang II (12 μg/kg/hr), Ang II (12 μg/kg/hr)+PD123319 (10 mg/kg/day) were deliv-ered via an osmotic minipump (Alzet, model 2002) placed in the peritoneal cavity of apoE(-/-) mice. Echocardiographic measurements were made 6 days after the start of infusions in apoE(-/-) mice under light anesthesia. Hemodynamic measurements were made on the 7th day after the start of infusion.
Here we show that in young (10-wk-old) apoE(-/-) mice with scattering inflammatory CD68+ monocytes attachment to endothelia cells, aortic smooth muscle cell and endothelial cell AT2R-immunoreactivity was 40- and 26-fold higher, respectively, than in control C57BL/6 mice (P<0.001). In comparison with vehicle control animals (n=10), low Ang II infusion (12 μg/kg/hr for 7 days, n=9) that was subpressor in control C57BL/6 mice decreased MAP (P<0.01), cardiac systolic and diastolic wall stresses, index of MVO2 and Tau (P<0.05, P<0.001, P<0.05 and P<0.001 respectively) in young apoE(-/-) mice. These Ang II effects were abolished by AT2R antagonist PD123319 (n=7, 10mg/kg/day for 7 days). The combination of Ang II and PD123319 infusion, which mainly activate AT1R after AT2R blocked, down-regulated vascular AT2R mRNA, decreased left ventricle (LV) fraction shortening (P<0.05) and VCFr (P<0.05), and also resulted in dilated heart evidenced by increases in LV end-diastolic diameter and volume (P<0.05 and P<0.01 respectively), indicating that AT2R has protective effects on cardiac performance.
Taken together, these results, at the first time, suggest that cardiovascular AT2R is up-regulated and protects cardiovascular functions in atherosclerosis-prone young apoE(-/-) mouse.