UC San Diego

Chapter 1. Hb-O2 Binding Affinity Modulating Treatments Pharmaceutical modulation of Hb-O2 binding affinity may improve hypoxia tolerance and decrease sickling in Townes transgenic sickle cell disease (SCD) mice. Two voxelotor (GBT440) analogs, GBT1118 and GBT21601, were tested and found to increase Hb-O2 affinity without affecting oxygen-sensitive cortical tissue. When treated with either drug, SCD mice displayed greatly improved tolerance to hypoxia both with chronic and acute treatments. Additionally, increased Hb-O2 affinity improved cardiac function of SCD mice during hypoxia while also reducing red blood cell (RBC) sickling. Chapter 2. Exogenous Estradiol Treatments Sexual biases have long been observed in many cardiovascular diseases. Estrogen has been found to impart cardioprotective benefit and estradiol is known to play regulatory roles in hypoxia and inflammatory pathway. Chronic treatments of estradiol were administered to female mice to determine if there are significant changes when compared to either male or untreated female mice during both hypoxia and sepsis. Exogenous estradiol treatments may improve cardiac function during hypoxia as well as induce changes in lipid and fatty acid production that may provide a protection during sepsis and inflammatory response.