Novel synthetic flavonoids in acute and chronic heart and kidney diseases

Abstract

© 2012 Dr. Fay Lin KhongCardiovascular disease remains one of the leading causes of death worldwide despite the dramatic reduction in mortality rates over the past two decades due to significant advancement in medical and public health interventions. Diabetes exacerbates the complex interaction of cardiovascular risk factors, resulting in the greater incidence of heart failure among individuals with diabetes when compared to those without diabetes. The relative risk of cardiovascular mortality is further increased when individuals with diabetes are diagnosed with the comorbidity of established chronic kidney disease. Therefore, there is a continuous need for the development of novel therapeutic strategies to prevent the progression of cardiac and renal dysfunction in the presence or absence of diabetes, since the protective effects from the routine use of current pharmacotherapy for the management of elevated blood glucose, high blood pressure and abnormal blood lipid profiles remain limited and controversial. The focus of this thesis is to further elucidate the pathophysiological roles of oxidative stress and inflammation in the disease progression and to explore the therapeutic potential of novel synthetic flavonoids, DiOHF and NP202, in the prevention of acute and chronic heart and kidney diseases. Cardiovascular disease remains one of the leading causes of death worldwide despite the dramatic reduction in mortality rates over the past two decades due to significant advancement in medical and public health interventions. Diabetes exacerbates the complex interaction of cardiovascular risk factors, resulting in the greater incidence of heart failure among individuals with diabetes when compared to those without diabetes. The relative risk of cardiovascular mortality is further increased when individuals with diabetes are diagnosed with the comorbidity of established chronic kidney disease. Therefore, there is a continuous need for the development of novel therapeutic strategies to prevent the progression of cardiac and renal dysfunction in the presence or absence of diabetes, since the protective effects from the routine use of current pharmacotherapy for the management of elevated blood glucose, high blood pressure and abnormal blood lipid profiles remain limited and controversial. The focus of this thesis is to further elucidate the pathophysiological roles of oxidative stress and inflammation in the disease progression and to explore the therapeutic potential of novel synthetic flavonoids, DiOHF and NP202, in the prevention of acute and chronic heart and kidney diseases. The manifestation of acute myocardial infarction remains a major contributor to the subsequent development of heart failure despite the successful implementation of coronary reperfusion strategies. There has been substantial evidence showing that the dynamic progression of LV contractile dysfunction persisted up to several weeks following the restoration of coronary blood flow. The oral administration of NP202 during the reperfusion period in an experimental model of AMI resulted in the sustained improvement of LV contractile function in association with the reduction in the accumulation of inflammatory cells in the infarct zone of the heart even after seven days following the induction of AMI. This thesis has provided a strong basis for further therapeutic advancement of synthetic flavonoids as novel pharmacological agents to prevent the progression of heart and kidney diseases in the absence and presence of diabetes. There are clear indications that the modulation of oxidative stress and inflammation in the presence of synthetic flavonoids could be responsible for the prevention of the disease progression. The comprehensive understanding of the pharmacokinetics and oral bioavailability of the synthetic flavonoids is necessary for further preclinical evaluation of these promising therapeutic interventions. The enhancement of the biological actions of the synthetic flavonoids in the oral formulation would thus enable the translation of the basic research for potential clinical utility