Creating a mouse model resistant to induced ischemic stroke and cardiovascular damage.

ABSTRACT: Vascular prostanoids, isomerized from an intermediate prostaglandin (PG), H₂, produced by cyclooxygenase (COX), exert various effects on the vascular system, both protective and destructive. During endothelial dysfunction, vascular protector prostacyclin/prostaglandin I₂ (PGI₂) is decreased, while inflammatory PGE₂ and thrombotic TXA₂ are increased. Therefore, our research aim was to reverse the event by controlling PGH₂ metabolism by generating an in vivo model via enzymatic engineering of COX-1 and prostacyclin synthase (PGIS). The COX-1 and PGIS genes were linked to a 10-residue amino acid linker to form a Single-chain Enzyme Complex (SCHEC), COX-1-10aa-PGIS. Transgenic (CP-Tg) mice in a FVB/N background were generated using the pronuclear microinjection method. We first confirmed mRNA and protein expression of COX-1-10aa-PGIS in various CP-Tg mouse tissues, as well as upregulation of circulating PGI₂. We then examined the cardiovascular function of these mice. Our CP-Tg mice exhibited marked resistance to vascular assault through induced carotid arterial blockage, acute thrombotic stroke and arterial arrest, angiotensin-induced peripheral vasoconstriction, and hepatic lipid accumulation after receiving a high-fat diet. They also had a longer lifespan compared with wild-type mice. This study raises the possibility of fighting cardiovascular diseases by regulating cellular arachidonic acid-derived PGH₂ metabolites using enzymatic engineering.

SUBMITTER: Ling QL 

PROVIDER: S-EPMC5786049 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature