Atorvastatin increases oxidative stress and modulates angiogenesis in Ossabaw swine with the metabolic syndrome Nassrene Y. Elmadhun, MD, Antonio D.

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Atorvastatin increases oxidative stress and modulates angiogenesis in Ossabaw swine with the metabolic syndrome Nassrene Y. Elmadhun, MD, Antonio D. Lassaletta, MD, Louis M. Chu, MD, Yuhong Liu, MD, Jun Feng, MD, Frank W. Sellke, MD The Journal of Thoracic and Cardiovascular Surgery Volume 144, Issue 6, Pages 1486-1493 (December 2012) DOI: 10.1016/j.jtcvs.2012.08.065 Copyright © 2012 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 Myocardial perfusion and coronary microvessel reactivity. A, Myocardial perfusion at rest and with demand pacing. No difference was seen in myocardial perfusion at rest or during demand pacing at 160 beats/min. B, Microvessel reactivity. No difference was seen in microvessel reactivity to endothelium-dependent (adenosine diphosphate [ADP]) or endothelium-independent (sodium nitroprusside [SNP]) vasodilators in oral hypercaloric/hypercholesterolemic diet (OHC) and oral hypercaloric/hypercholesterolemic diet plus 1.5 mg/kg atorvastatin daily (OHCS) groups. C, Baseline microvessel diameter and percentage of preconstriction. No difference was seen in baseline diameter or percentage of preconstriction in ADP- or SNP-treated microvessels. The Journal of Thoracic and Cardiovascular Surgery 2012 144, 1486-1493DOI: (10.1016/j.jtcvs.2012.08.065) Copyright © 2012 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 Atorvastatin and angiogenesis. A, Endothelial cell density staining for CD31. Significant increase seen in capillary density in oral hypercaloric/hypercholesterolemic diet plus 1.5 mg/kg atorvastatin daily (OHCS) compared with oral hypercaloric/hypercholesterolemic diet (OHC) groups. B, Arteriolar density staining for smooth muscle actin. No significant increase was seen in arteriolar density in OHCS group compared with OHC. C, Western blot analysis of angiogenesis protein expression showing a significant increase in proangiogenic proteins endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (peNOS), phosphorylated adenosine monophosphate kinase (pAMPK), phosphorylated extracellular signal-regulated kinase (pERK), and vascular endothelial growth factor (VEGF) and a significant decrease in Akt and phosphorylated Akt (pAkt). Also, a trend was seen toward decreased anti-angiogenesis protein angiostatin. ∗P < .05 and ∗∗P < .01. AMPK, Adenosine monophosphate kinase; HPF, high power field; VEGFR2, VEGF receptor 2. The Journal of Thoracic and Cardiovascular Surgery 2012 144, 1486-1493DOI: (10.1016/j.jtcvs.2012.08.065) Copyright © 2012 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Oxidative stress profile. A, Myocardial protein oxidation showing significantly increased protein oxidation in oral hypercaloric/hypercholesterolemic diet plus 1.5 mg/kg atorvastatin daily (OHCS) compared with oral hypercaloric/hypercholesterolemic diet (OHC) groups. B, Serum lipid peroxidation. Significantly increased lipid peroxidation was seen in OHCS group compared with OHC group. C, Western blot analysis of oxidative stress protein expression showing no difference in expression of proteins involved in oxidative stress. ∗P < .05. AMPK, Adenosine monophosphate kinase; eNOS, endothelial nitric oxide synthase; pAkt, phosphorylated Akt; pAMPK, phosphorylated AMPK; peNOS, phosphorylated eNOS; VEGF, vascular endothelial growth factor; VEGFR2, VEGF receptor 2. The Journal of Thoracic and Cardiovascular Surgery 2012 144, 1486-1493DOI: (10.1016/j.jtcvs.2012.08.065) Copyright © 2012 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 Picosirius red and trichrome staining for collagen and intramyocardial fibrosis showing no difference in collagen area fraction or fraction of intramyocardial fibrosis in oral hypercaloric/hypercholesterolemic diet plus 1.5 mg/kg atorvastatin daily (OHCS) compared with oral hypercaloric/hypercholesterolemic diet (OHC) groups. The Journal of Thoracic and Cardiovascular Surgery 2012 144, 1486-1493DOI: (10.1016/j.jtcvs.2012.08.065) Copyright © 2012 The American Association for Thoracic Surgery Terms and Conditions