Mechanisms Underlying Vascular Aging

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Abstract Aortic stiffness is considered a growing epidemic and has emerged as an important risk factor for various cardiovascular diseases (CVD). African Americans have the highest incidence rates of CVD and studies have shown that aortic stiffness is also higher among AAs compared to Caucasians. Very little is known about the molecular mechanism of aortic stiffness in AAs. A potential cause for the increased risk of aortic stiffness in African Americans is genetics. Populations of African ancestry have more genetic variation and less correlation between physically close genetic variants than other populations which means that, in addition to shared variation across populations, there remains population-specific genetic variation that contributes to disease. The rho-associated coiled-coil forming kinases (ROCK1 and ROCK2) have been shown to play a critical role in many cardiovascular diseases and increased ROCK activity has been associated with advancing age, systolic hypertension, and other cardiovascular risk factors such as obesity and smoking. Furthermore, increased ROCK activity correlates with aortic stiffness and vascular dysfunction, and treatment with the ROCK inhibitor, fasudil, improves vasomotor function in humans. These findings suggest that ROCKs may play an important role in the pathogenesis of aortic stiffness. But our knowledge of the molecular mechanisms regulating ROCK activity is limited and furthermore, we do not know if there are population-specific genetic modifiers of ROCK activity. The focus of the proposed study is to identify genetic modifiers of ROCK activity and elucidate molecular mechanisms leading to aortic stiffness in African Americans. Increased ROCK activity may increase risk of aortic stiffness in African Americans and furthermore, genetic modifiers of ROCK activity may be associated with aortic stiffness. The results generated from our project will advance our understanding of genetic modifiers of ROCK activity and risk factors of aortic stiffness in African Americans. Translational research that integrates population-specific genomic variation and complexity has tremendous potential to reduce health disparities and improve clinical practice. This study will harness the latest advances in bioinformatics and genomics to better understand the etiology of ROCK activity and aortic stiffness and serve as a platform so that prevention, diagnosis and treatment are precisely tailored to individuals – making precision medicine a reality for African American stroke patients.