| dc.description.abstract | Apelin is an endogenous ligand for APJ receptors, which are highly expressed throughout
the cardiovascular system, including coronary arteries. Apelin causes endothelium‐derived nitric
oxide (NO) –dependent relaxation of coronary arteries under physiological conditions, but little is
known about regulation of coronary vasomotor tone by apelin under pathological conditions. This
research addresses the critical gap in understanding of the apelin signaling in coronary circulation
under normal and pathological conditions.
Evidence from this study suggests that apelin could not provide beneficial vasodilatory
effects in hypertensive coronary arteries. Moreover, apelin impairs endothelium-dependent
relaxations to vasodilator, acetylcholine. Impaired apelin-APJ signaling in hypertensive coronary
arteries is possibly through defective production or release of NO from coronary endothelial cells
rather than inhibiting effects of NO in coronary arterial smooth muscle cells.
My next aim was to understand the mechanisms involved in the loss of apelin response in
hypertensive arteries. The results suggested that the APJ receptor signaling via GRK2 pathway is
possibly responsible for the impaired apelin response in hypertensive coronary arteries.
Interestingly, APJ receptor biased agonist, CMF-019, -induced relaxation in hypertensive coronary
arteries and showed no effects on vasodilatory response to acetylcholine. My results also suggest
the possible impairment of PI3K/AKT/eNOS pathway mediated by GRK2 activation in
hypertensive coronary arteries.
My final aim was to check whether apelin signaling is impaired in coronary arteries only
under hypertensive conditions or if it occurs in other disease conditions. My data suggests that
apelin signaling is impaired in coronary arteries exposed to cigarette smoke extract (CSE), a model
for secondhand smoke exposure. Interestingly, similar to hypertensive coronary arteries, apelin lost its beneficial vasodilatory effects possibly through the GRK2 activation in CSE treated
coronary arteries.
Overall, this research provides evidence that apelin behaves differently under physiological
and pathological conditions. As a point of fact, apelin not only lost its beneficial effects but also
might have negative effects under pathological conditions such as hypertension and secondhand
smoke exposure. I anticipate that the results from this approach will be useful in improving the
therapeutic strategies with apelin and other APJ receptor agonists that are aimed to alleviate
different cardiovascular disorders. | en_US |
