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

• Published in: Scientific reports Vol. 8; no. 1; pp. 1653 - 12
• Main Authors: Ling, Qing-Lan, Mohite, Anita J, Murdoch, Emma, Akasaka, Hironari, Li, Qun-Ying, So, Shui-Ping, Ruan, Ke-He
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 26.01.2018; Nature Publishing Group UK
• Subjects: Amino acids; Angiotensin; Animals; Arachidonic acid; Cardiovascular diseases; Cyclooxygenase 1 - genetics; Cyclooxygenase 1 - metabolism; Cyclooxygenase-1; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Disease Models, Animal; Disease Resistance; Gene expression; High fat diet; Inflammation; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - metabolism; Ischemia; Life span; Metabolites; Mice; Mice, Transgenic; Microinjection; mRNA; Myocardial Infarction - pathology; Myocardial Infarction - prevention & control; Prostacyclin; Prostacyclin synthase; Prostaglandin E2; Prostaglandins; Rodents; Stroke - pathology; Transgenic mice; Vascular system; Vasoconstriction
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-19661-y

Vascular prostanoids, isomerized from an intermediate prostaglandin (PG), H , produced by cyclooxygenase (COX), exert various effects on the vascular system, both protective and destructive. During endothelial dysfunction, vascular protector prostacyclin/prostaglandin I (PGI ) is decreased, while inflammatory PGE and thrombotic TXA are increased. Therefore, our research aim was to reverse the event by controlling PGH 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 PGI . 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 PGH metabolites using enzymatic engineering.