The cardiac sodium-calcium exchanger (NCX) is an important membrane protein which regulates cellular calcium necessary for the optimal contractile function of the heart. NCX has become a focal point in ischemic heart disease (IHD) research as evidence suggests that reactive oxygen species (ROS) produced during IHD can cause NCX to malfunction resulting in an intracellular calcium overload leading to cardiac contractile abnormalities. Therefore, I hypothesized that NCX function is mediated by ROS increasing NCX1 activity during cardiac ischemia-reperfusion. To research this hypothesis, I investigated cellular mechanisms which may play a role in NCX dysfunction and also examined methods to correct NCX function. I found that reactive oxygen species directly and irreversibly modify NCX protein, increasing its activity, thereby worsening the calcium overload which is deleterious to cardiac function. I also elucidated the molecular means by which NCX protein modification occurs. Exploring pharmacological means by which to decrease NCX function to relieve the calcium overload and reduce the damage to the heart, I discovered that ranolazine (Ranexa), indicated for the treatment of angina pectoris inhibits NCX activity directly, thereby further reducing the calcium overload-induced injury to the heart.
Furthermore, many IHD patients are also co-morbid for type-2 diabetes. These patients are prescribed sulfonylurea (SU) agents which act at the ATP sensitive K+ channel (KATP). One agent such as glibenclamide is known to have
cardiotoxic side effects. Therefore, SUs devoid of any cardiac side effects would beneficial. Interestingly, patients possessing the genetic variant E23K-S1369A KATP channel have improved blood glucose levels with the use of the SU gliclazide. Therefore, I determined the functional mechanism by which gliclazide has increased inhibition at the KATP channel. These findings have implications for type-2 diabetes therapy, in which 20% of the type-2 diabetic population carries the KATP channel variant.
In summary, the findings presented in this thesis have implications on treatment strategies in the clinical setting, as a NCX inhibitor can be beneficial in IHD and possibly type-2 diabetes. Moreover, a pharmacogenomic approach in treating type-2 diabetes may also provide a positive outcome when considering co-morbid cardiac complications such as atrial fibrillation and heart failure.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/1629 |
| Date | 06 1900 |
| Creators | Soliman, Daniel |
| Contributors | Light, Peter E. (Pharmacology), Clanachan, Alexander S. (Pharmacology), Seubert, John M. (Pharmacy and Pharmaceutical Sciences), Fliegel, Larry (Biochemistry), Pierce, Grant N. (Physiology & Pharmacology, University of Manitoba, Winnipeg, MB) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 4356018 bytes, application/pdf |
| Relation | Soliman D., Hamming K.S.C., Matemisz L.C., Light P.E. (2009). Reactive Oxygen Species Directly Modify Sodium-Calcium Exchanger Activity in a Splice-Variant Dependent Manner. Journal of Molecular & Cellular Cardiology 47, 595-602., *Hamming K.S.C., *Soliman D., Matemisz L.C., Niazi O., Lang V., Gloyn G.L., Light P.E. (2009). Co-expression of the Type-2 Diabetes Susceptibility Gene Variants KCNJ11 E23K and ABCC8 S1369A Alter the ATP and Sulfonylurea Sensitivities of the ATP-Sensitive K+ Channel. Diabetes 58, 2419-2424. (*denotes equal contributions). |
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