Identification of Novel Therapeutic Targets of RhoBTB1-Cullin 3 Pathway in Cardiovascular Disease

Project Description Narrative:

Hypertension (HTN) is a predominant risk factor for the development of many cardiovascular diseases (CVDs). Elevation in blood pressure directly correlates with increased risk of developing life-threatening CV events including heart failure and stroke. The lifetime risk of heart failure is twice in hypertensive subjects as compared to the subjects with blood pressure less than 140/90 mmHg.

In 2019, HTN was the primary or contributing cause of 0.5 million deaths in the U.S. The treatment of high blood pressure also leads to significant economic burden; as averaged over 12 years from 2003 to 2014, the annual cost of HTN treatment was $31 billion. The scenario of HTN in Wisconsin is no better, as only 50% of adults in the state have their blood pressure under control. Shockingly, one in six adults is not aware of having HTN. 36% of men and 47% of women over 45 years of age will die within five years after their first heart attack. Currently available anti-hypertensive therapeutics are well-proven to restrain HTN and its associated outcomes, but they have off-target effects, and their long-term use is a matter of concern. For example, diuretics, a gold standard in management of HTN, is linked with increased incidence of impaired glucose tolerance and developing diabetes mellitus. Similarly, calcium antagonists are accused of increased risk of cancer in hypertensive subjects. Moreover, drug resistance and lack of drug adherence are additional hurdles associated with currently available anti-hypertensive drugs.

Therefore, therapeutic efforts to lower the HTN-associated cardiovascular mortality represent a constant need and justifies efforts to identify new antihypertensive therapeutic strategies. This is only possible by discovering potential therapeutic targets and antihypertensive therapeutic regimens with lesser or minimal side effects and maximum CV benefits. This approach can improve the feasibility of implementing the research findings in real-world settings of the U.S. population. This project will advance several aspects in cardiovascular physiology. The long-term goals will be to apply this knowledge to assess the function of RhoBTB1 binding proteins as regulators of vascular function and blood pressure. The research team has determined that RhoBTB1 has many binding partners and some of these appear to be important for modulating blood pressure and arterial stiffness. The purpose of this project is to identify the full range of RhoBTB1 targets with the goal of increasing the opportunities for developing novel therapeutics.