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Cell Biology and Molecular Medicine Program
B.M. 2001, Shanghai Second Medical University
Thesis Advisor: Stephen F. Vatner, M.D.
Department of Cell Biology and Molecular Medicine
Tuesday, March 20, 2012
1:00 P.M., MSB-G609
Hypothesis: Overexpression of ƒÑ1A-adrenergic receptors (ƒÑ1A-ARs) protects the heart from acute and chronic myocardial ischemia through second window ischemic preconditioning and angiogenesis.
Rationale: Studies with pharmacological stimulation of alpha adrenergic receptors and overexpression of them in the heart in transgenic mice have identified a role in ischemic cardioprotection, but the role of the specific alpha1A-adrenergic receptor subtype is not established, particularly with regard to mechanisms mediating cardioprotection and whether it is involved in a specific window of ischemic preconditioning. To elucidate these mechanisms we utilized a novel transgenic rat model with cardiac ƒÑ1A-AR overexpression, which permitted direct and continuous measurements of cardiac function in unanesthetized rats.
Methods and Results: Cardiac specific overexpressed ƒÑ1A-adrenergic receptor rats exhibited increased inotropy, improved lusitropy and negative chronotropy with similar LV triple product (LV systolic wall stress x LV +dP/dt x heart rate). When the animals were treated with 30 min ischemia followed by 3hr reperfusion (I/R), infarct size (IS)/area at risk (AAR) was significantly reduced in TGs compared to non-transgenic littermates (NTLs) (p<0.05). With second window ischemic preconditioning (IPC) IS/AAR fell in NTLs, but in ƒÑ1A-TGs. In contrast, with first window preconditioning, IS/AAR was reduced to a similar level in both ƒÑ1A-TGs and NTLs, which were much lower than ƒÑ1A-TGs without preconditioning. Cardioprotection in untreated ƒÑ1A-TGs was associated with enhanced myocardial inducible nitric oxide synthase (iNOS), COX2, phosphorylated (p)-Akt and p-MEK, p-ERK at the protein level, along with an increase in total NOS activity, which are pathognomonic for second window preconditioning. In the presence of a non-selective NOS inhibitor, L-NNA, or MEK inhibitor, U0126, the reduction in infarct size in transgenic rats after ischemia/reperfusion was abolished and the protective effects of ƒÑ1A-AR overexpression were abrogated. Moreover, with the ƒÑ1-antagonist, prazosin, both NTLs and TGs did not show any further reduction in infarct size after 2nd window IPC. Consistent with the observed phenotypic protection against ischemic injury, Affymetrix microarray revealed similar gene expression between NTL treated with 2nd window IPC and baseline ƒÑ1A-AR overexpressed TG heart. 4 weeks after ligation of the left anterior descending coronary artery, the scar size of TG rats were found to be lower than NTLs, with angiogenesis and myocyte proliferation. Angiogenesis in TG rats was also increased at baseline with a significantly increased vessel density and more Ki-67 positive capillaries compared to NTLs. Furthermore, angiogenesis related genes, such as VEGF-A, HIFƒÑ, Itgb3 were markedly upregulated.
Conclusion: ƒÑ1A-AR overexpression 1) improves cardiac function at baseline; 2) protects the heart against acute ischemic injury via the Akt/MEK/ERK/iNOS pathway; 3) phenocopies second, but not first, window ischemic preconditioning; 4) induces angiogenesis and protects the heart against chronic ischemia associated remodeling by myogenesis and angiogenesis.