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

Area of Science:

• Biochemistry
• Molecular Biology
• Cardiovascular Science

Background:

• Vascular prostanoids, derived from prostaglandin H2 (PGH2) via cyclooxygenase (COX), have dual protective and destructive roles.
• Endothelial dysfunction involves decreased protective prostacyclin I2 (PGI2) and increased inflammatory prostaglandin E2 (PGE2) and thrombotic thromboxane A2 (TXA2).

Purpose of the Study:

• To engineer an in vivo model for controlling PGH2 metabolism by enzymatically linking COX-1 and prostacyclin synthase (PGIS).
• To investigate the therapeutic potential of enhanced PGI2 production for cardiovascular disease prevention.

Main Methods:

• Constructed a Single-chain Enzyme Complex (SCHEC) by linking COX-1 and PGIS genes with a 10-amino acid linker (COX-1-10aa-PGIS).
• Generated transgenic (CP-Tg) mice using pronuclear microinjection and confirmed gene and protein expression.
• Assessed cardiovascular function and disease resistance in CP-Tg mice.

Main Results:

• Confirmed successful expression of COX-1-10aa-PGIS and elevated circulating PGI2 levels in CP-Tg mice.
• CP-Tg mice demonstrated significant resistance to induced carotid arterial blockage, thrombotic stroke, arterial arrest, and angiotensin-induced vasoconstriction.
• Mice showed reduced hepatic lipid accumulation on a high-fat diet and exhibited a longer lifespan compared to wild-type controls.

Conclusions:

• Enzymatic engineering of COX-1 and PGIS can effectively modulate PGH2 metabolism in vivo.
• This approach enhances protective PGI2 production, offering a novel strategy for combating cardiovascular diseases.
• Regulating arachidonic acid-derived metabolites through enzymatic engineering holds promise for cardiovascular health.