Rosuvastatin Decreases Caveolin-1 and Improves Nitric Oxide–Dependent Heart Rate and Blood Pressure Variability in Apolipoprotein E ^−/− Mice In Vivo

Abstract

Background-Decreased heart rate variability (HRV) and increased blood pressure variability (BPV), determined in part by nitric oxide (NO)-dependent endothelial dysfunction, are correlated with adverse prognosis in cardiovascular diseases. We examined potential alterations in BPV and HRV in genetically dyslipidemic, apolipoprotein (apo) E Ϫ/Ϫ , and control mice and the effect of chronic statin treatment on these parameters in relation to their NO synthase (NOS)-modifying properties. Methods and Results-BP and HR were recorded in unrestrained, nonanesthetized mice with implanted telemetry devices with or without rosuvastatin. Cardiac and aortic expression of endothelial NOS and caveolin-1 were measured by immunoblotting. Both systolic BP and HR were elevated in apoE Ϫ/Ϫ mice, with abolition of their circadian cycles. Spectral analysis showed an increase in their systolic BPV in the very-low-frequency (ϩ17%) band and a decrease in HRV in the high-frequency (Ϫ57%) band, reflecting neurohumoral and autonomic dysfunction. Decreased sensitivity to acute injection of atropine or an NOS inhibitor indicated basal alterations in both parasympathetic and NOS regulatory systems in apoE Ϫ/Ϫ mice. Aortic caveolin-1 protein, an inhibitor of endothelial NOS, was also increased in these mice by 2.0-fold and correlated positively with systolic BPV in the very-low-frequency band. Rosuvastatin treatment corrected the hemodynamic and caveolin-1 expression changes despite persisting elevated plasma cholesterol levels. Conclusions-Rosuvastatin

Weight Loss–Associated Induction of Peroxisome Proliferator–Activated Receptor-α and Peroxisome Proliferator–Activated Receptor-γ Correlate With Reduced Atherosclerosis and Improved Cardiovascular Function in Obese Insulin-Resistant Mice

“…19 We and others have shown that the NOS pathway is a major "buffering" system of systolic BP and that chronic dyslipidemia specifically alters endothelial NO synthesis, with a resultant increased variability of SBP. 18,19 An important observation in our study is that diet restriction and weight loss normalized BP, restored BP circadian variation, and normalized BP and HR variability in the VLF, LF, and HF bands, respectively ( Figure 6). The increased variability of BP in free-fed DKO mice and the decrease of this variability on weight loss are potentially clinically important observations, given the adverse prognosis associated with increased SBP variability in humans.…”

“…The area under the curve was calculated for the very-low-frequency (VLF, 0.05 to 0.4 Hz), low-frequency (LF, 0.4 to 1.5 Hz), and high-frequency (HF, 1.5 to 5.0 Hz) bands as previously defined in the mouse. [17][18][19] Spectral variability at each bandwidth was normalized to the total spectral area.…”

Induction of the Cytoprotective Enzyme Heme Oxygenase-1 by Statins Is Enhanced in Vascular Endothelium Exposed to Laminar Shear Stress and Impaired by Disturbed Flow

“…Moreover, inhibition of cholesterol synthesis by statins may reduce caveolin-1 expression through changes in sterol regulatory element activity. This reduces caveolin-1-mediated inhibition of eNOS activity (48,49), and hence may play a role in the HO-1 induction observed herein. In contrast, cyclosporin A reduced EC cholesterol and inhibited eNOS phosphorylation (54).…”

Statins as Regulators of Redox State in the Vascular Endothelium: Beyond Lipid Lowering

“…Atorvastatin reduces caveolin-1 content and activates eNOS in ECs irrespective of the presence or absence of LDL cholesterol (18). This mechanism has also been demonstrated in apolipoprotein E (ApoE)-deficient mice, where rosuvastatin reduces caveolin-1 content and improves heart and blood pressure variability (84).…”