Liposomal delivery of the cyp1b1 enzyme inhibitor, 2,3’,4,5’- tetramethoxystilbene, for improved vasodilator responses in hypertension

Zaabalawi, Azziza Ziad (2022) Liposomal delivery of the cyp1b1 enzyme inhibitor, 2,3’,4,5’- tetramethoxystilbene, for improved vasodilator responses in hypertension. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

Systemic hypertension is a leading risk factor for cardiovascular disease mortality, associated with compromised vasodilator function and increased oxidative stress. The cytochrome P450 enzyme, CYP1B1, plays a significant role in the development of hypertension, via increased synthesis of the potent vasoconstrictor 20-HETE and subsequent generation of NADPH oxidase-derived reactive oxygen species (ROS). 2, 3’, 4, 5’-Tetramethoxystilbene (TMS) is a potent inhibitor of CYP1B1, however, it has a low bioavailability. Liposomes are recognised as promising delivery systems that can be used for the encapsulation of TMS to improve bioavailability. This study aimed to investigate TMS-loaded liposomes as a promising therapeutic strategy to restore the dilator responses of arteries exposed to an elevated oxidative stress environment, in hypertension. TMS-loaded liposomes (157 ± 6 nm) were characterised using a range of chemical techniques. The effects of TMS-loaded liposomes on vasodilator function were examined, using isolated rat aortic and coronary vessels exposed to an oxidative stress environment within an ex vivo model of acute hypertension, and internal mammary arteries (IMAs) harvested from hypertensive coronary artery bypass graft patients, and assessed mechanisms involved. Liposomal delivery of TMS improved its bioavailability (compared to TMS solution). TMS-loaded liposomes restored the magnitude of dilation of aortic and coronary arteries, via a reduction in NADPH oxidase-derived ROS and potentiation of NO and EDH, mediated by AMPK, and alleviated the attenuated vasodilation of human IMAs, by reducing both cytosolic and mitochondrial superoxide anion levels, and restoring NO bioavailability. Our novel findings have important implications in the potential use of liposomal encapsulated TMS as a therapeutic intervention strategy to restore vasodilator capacity in hypertension.