{"id":{"repo_id":"vcu","oai_identifier":"oai:scholarscompass.vcu.edu:etd-2073"},"canonical_url":"https://search.dev.ndltd.org/etd/vcu/oai:scholarscompass.vcu.edu:etd-2073","repository":{"repo_id":"vcu","name":"Virginia Commonwealth University","base_url":"https://scholarscompass.vcu.edu/do/oai/"},"display":{"title":"Divergent Roles of PI3K and Akt in Rapamycin-induced Cardioprotection against Ischemia-Reperfusion Injury","abstract":"Coronary heart disease (CHD) is one of the leading causes of death every year with nearly three-fourths of all deaths caused by the disease. The challenge scientists are facing today is discovering new drugs to protect the heart against cellular damage caused by ischemia-reperfusion injury (I-R injury). Rapamycin is one such drug that has been shown to protect the heart against ischemia-induced cellular injury. Rapamycin(sirolimus) inhibits protein synthesis through inhibition of the mammalian target ofrapamycin (mTOR). This property of rapamycin has led to its current clinical applications in drug-eluting stents and in immunosuppresive treatment to organ transplant patients. The mechanism by which this drug protects against I-R injury is currently unknown. The goal of this study is to elucidate rapamycin's cardioprotective signaling pathway. We hypothesized that upregulation of Akt occurs possibly as part of a positive feedback mechanism following the inhibition of mTOR by rapamycin. Adult male ICRmice were treated with rapamycin (0.25 mg/kg, i.p.), or volume-matched DMSO (solvent for rapamycin), or rapamycin (0.25mg/kg, i.p.) plus wortmannin (WTN, 15µg/kg, i.p.),an inhibitor of phosphatidylinositol 3-kinase, or wortmannin alone (15µg/kg, i.p.). After 30 min of stabilization, the hearts were subjected to 20 minutes of global ischemia and 30 minutes of reperfusion in Langendorff model. In a separate series of experiments mice were either injected with DMSO or rapamycin for 30 minutes, 1 hour, and 2 hours before harvesting the hearts for Western blot analysis of levels of total or phosphorylated Akt at Ser473. Our results showed that rapamycin protected the heart as observed by a reductionin infarct size from 33.8 ± 2.0% in DMSO-treated hearts to 19.3 ± 4.1% in rapamycin-treated hearts; a 43% reduction. This infarct-limiting effect was completely blocked by wortmannin (29.3 ± 4.8%). However, Western blot analysis showed no change in the level of Akt phosphorylation after administration of rapamycin. Our current resultsfurther confirmed rapamycin as a potential cardio-therapeutic drug to limit infarct size,potentially through the PI3K signaling pathway. However, the exact signaling pathway of this protection still remains elusive.","abstract_html":"Coronary heart disease (CHD) is one of the leading causes of death every year with nearly three-fourths of all deaths caused by the disease. The challenge scientists are facing today is discovering new drugs to protect the heart against cellular damage caused by ischemia-reperfusion injury (I-R injury). Rapamycin is one such drug that has been shown to protect the heart against ischemia-induced cellular injury. Rapamycin(sirolimus) inhibits protein synthesis through inhibition of the mammalian target ofrapamycin (mTOR). This property of rapamycin has led to its current clinical applications in drug-eluting stents and in immunosuppresive treatment to organ transplant patients. The mechanism by which this drug protects against I-R injury is currently unknown. The goal of this study is to elucidate rapamycin's cardioprotective signaling pathway. We hypothesized that upregulation of Akt occurs possibly as part of a positive feedback mechanism following the inhibition of mTOR by rapamycin. Adult male ICRmice were treated with rapamycin (0.25 mg/kg, i.p.), or volume-matched DMSO (solvent for rapamycin), or rapamycin (0.25mg/kg, i.p.) plus wortmannin (WTN, 15µg/kg, i.p.),an inhibitor of phosphatidylinositol 3-kinase, or wortmannin alone (15µg/kg, i.p.). After 30 min of stabilization, the hearts were subjected to 20 minutes of global ischemia and 30 minutes of reperfusion in Langendorff model. In a separate series of experiments mice were either injected with DMSO or rapamycin for 30 minutes, 1 hour, and 2 hours before harvesting the hearts for Western blot analysis of levels of total or phosphorylated Akt at Ser473. Our results showed that rapamycin protected the heart as observed by a reductionin infarct size from 33.8 ± 2.0% in DMSO-treated hearts to 19.3 ± 4.1% in rapamycin-treated hearts; a 43% reduction. This infarct-limiting effect was completely blocked by wortmannin (29.3 ± 4.8%). However, Western blot analysis showed no change in the level of Akt phosphorylation after administration of rapamycin. Our current resultsfurther confirmed rapamycin as a potential cardio-therapeutic drug to limit infarct size,potentially through the PI3K signaling pathway. However, the exact signaling pathway of this protection still remains elusive.","abstract_has_math":false,"creators":["Desai, Shivani Kirit"],"institution":null,"degree_name":"Master of Science","degree_level":"Thesis","degree_discipline":"Physiology","degree_department":null,"school":null,"contributors":["Dr. Rakesh Kukreja"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2007,"date_issued":"2007-01-01T08:00:00Z","date_published":"2007-01-01T08:00:00Z","updated_at":"2026-07-24T05:54:47Z","subjects":["Langendorff isolated heart model","Akt","PI3K","rapamycin","wortmannin","Life Sciences","Physiology"],"languages":[],"rights":["© The Author"],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["https://scholarscompass.vcu.edu/etd/1074"],"render_values":[{"text":"https://scholarscompass.vcu.edu/etd/1074","href":"https://scholarscompass.vcu.edu/etd/1074","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.25772/MSJA-DN40","outbound_label":"DOI","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Dr. Rakesh Kukreja"]},{"key":"dc:creator","label":"Author","values":["Desai, Shivani Kirit"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2014-07-09T07:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Physiology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Thesis"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Master of Science"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Langendorff isolated heart model","Akt","PI3K","rapamycin","wortmannin","Life Sciences","Physiology"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["© The Author"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://doi.org/10.25772/MSJA-DN40","https://scholarscompass.vcu.edu/etd/1074"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Coronary heart disease (CHD) is one of the leading causes of death every year with nearly three-fourths of all deaths caused by the disease. The challenge scientists are facing today is discovering new drugs to protect the heart against cellular damage caused by ischemia-reperfusion injury (I-R injury). Rapamycin is one such drug that has been shown to protect the heart against ischemia-induced cellular injury. Rapamycin(sirolimus) inhibits protein synthesis through inhibition of the mammalian target ofrapamycin (mTOR). This property of rapamycin has led to its current clinical applications in drug-eluting stents and in immunosuppresive treatment to organ transplant patients. The mechanism by which this drug protects against I-R injury is currently unknown. The goal of this study is to elucidate rapamycin's cardioprotective signaling pathway. We hypothesized that upregulation of Akt occurs possibly as part of a positive feedback mechanism following the inhibition of mTOR by rapamycin. Adult male ICRmice were treated with rapamycin (0.25 mg/kg, i.p.), or volume-matched DMSO (solvent for rapamycin), or rapamycin (0.25mg/kg, i.p.) plus wortmannin (WTN, 15µg/kg, i.p.),an inhibitor of phosphatidylinositol 3-kinase, or wortmannin alone (15µg/kg, i.p.). After 30 min of stabilization, the hearts were subjected to 20 minutes of global ischemia and 30 minutes of reperfusion in Langendorff model. In a separate series of experiments mice were either injected with DMSO or rapamycin for 30 minutes, 1 hour, and 2 hours before harvesting the hearts for Western blot analysis of levels of total or phosphorylated Akt at Ser473. Our results showed that rapamycin protected the heart as observed by a reductionin infarct size from 33.8 ± 2.0% in DMSO-treated hearts to 19.3 ± 4.1% in rapamycin-treated hearts; a 43% reduction. This infarct-limiting effect was completely blocked by wortmannin (29.3 ± 4.8%). However, Western blot analysis showed no change in the level of Akt phosphorylation after administration of rapamycin. Our current resultsfurther confirmed rapamycin as a potential cardio-therapeutic drug to limit infarct size,potentially through the PI3K signaling pathway. However, the exact signaling pathway of this protection still remains elusive."]},{"key":"dc:title","label":"Title","values":["Divergent Roles of PI3K and Akt in Rapamycin-induced Cardioprotection against Ischemia-Reperfusion Injury"]}]}],"canonical_facts":{"dc:contributor":["Dr. Rakesh Kukreja"],"dc:creator":["Desai, Shivani Kirit"],"dc:date.available":["2014-07-09T07:00:00Z"],"dc:description.abstract":["Coronary heart disease (CHD) is one of the leading causes of death every year with nearly three-fourths of all deaths caused by the disease. The challenge scientists are facing today is discovering new drugs to protect the heart against cellular damage caused by ischemia-reperfusion injury (I-R injury). Rapamycin is one such drug that has been shown to protect the heart against ischemia-induced cellular injury. Rapamycin(sirolimus) inhibits protein synthesis through inhibition of the mammalian target ofrapamycin (mTOR). This property of rapamycin has led to its current clinical applications in drug-eluting stents and in immunosuppresive treatment to organ transplant patients. The mechanism by which this drug protects against I-R injury is currently unknown. The goal of this study is to elucidate rapamycin's cardioprotective signaling pathway. We hypothesized that upregulation of Akt occurs possibly as part of a positive feedback mechanism following the inhibition of mTOR by rapamycin. Adult male ICRmice were treated with rapamycin (0.25 mg/kg, i.p.), or volume-matched DMSO (solvent for rapamycin), or rapamycin (0.25mg/kg, i.p.) plus wortmannin (WTN, 15µg/kg, i.p.),an inhibitor of phosphatidylinositol 3-kinase, or wortmannin alone (15µg/kg, i.p.). After 30 min of stabilization, the hearts were subjected to 20 minutes of global ischemia and 30 minutes of reperfusion in Langendorff model. In a separate series of experiments mice were either injected with DMSO or rapamycin for 30 minutes, 1 hour, and 2 hours before harvesting the hearts for Western blot analysis of levels of total or phosphorylated Akt at Ser473. Our results showed that rapamycin protected the heart as observed by a reductionin infarct size from 33.8 ± 2.0% in DMSO-treated hearts to 19.3 ± 4.1% in rapamycin-treated hearts; a 43% reduction. This infarct-limiting effect was completely blocked by wortmannin (29.3 ± 4.8%). However, Western blot analysis showed no change in the level of Akt phosphorylation after administration of rapamycin. Our current resultsfurther confirmed rapamycin as a potential cardio-therapeutic drug to limit infarct size,potentially through the PI3K signaling pathway. However, the exact signaling pathway of this protection still remains elusive."],"dc:identifier":["https://doi.org/10.25772/MSJA-DN40","https://scholarscompass.vcu.edu/etd/1074"],"dc:rights":["© The Author"],"dc:subject":["Langendorff isolated heart model","Akt","PI3K","rapamycin","wortmannin","Life Sciences","Physiology"],"dc:title":["Divergent Roles of PI3K and Akt in Rapamycin-induced Cardioprotection against Ischemia-Reperfusion Injury"],"thesis:degree_discipline":["Physiology"],"thesis:degree_level":["Thesis"],"thesis:degree_name":["Master of Science"]},"updated_at":"2026-07-24T05:54:47Z"}