Resistant to thrombosis, induced stroke and heart arrest by incorporation of a single gene of PGI2-synthesizing COX-1-PGIS in vivo: Implication against human heart disease

Ruan, Ke‐He; Mohite, Anita; So, Shui-Ping

doi:10.1016/j.ijcard.2013.03.114

Cited by 5 publications

(8 citation statements)

References 10 publications

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“…Additionally, increased PGI 2 did not appear to be lethal, as all animals survived the duration of the study. In CP-Tg mice transgenic expression of the hybrid enzyme, COX-1-10aa-PGIS, occurs in all major organ systems, including the CNS [21]. Consequently, it is possible that the changes in cognitive and non-cognitive behaviors we observed in CP-Tg mice could result from increased PGI 2 production from both within the CNS and peripherally.…”

Section: Discussionmentioning

confidence: 99%

“…All experiments were conducted in accordance with the University of Houston IACUC guidelines using approved protocols. CP-Tg mice were genotyped using PGIS-specific primers (BD2442-1:GGATTCCAAGTCTCCACCC; BD2442-2: GCAGTCACACTGGTAGCGG) [21]. …”

Section: Methodsmentioning

confidence: 99%

“…CP-Tg mice overexpress the TriCat enzyme [20, 21], a hybridized enzyme linking COX-1 and PGIS via a transmembrane domain. Overexpression of this hybrid results in a three-fold increase in anabolism of PGI 2 in cell lines and shows an increased ability to efficiently convert AA into PGI 2 [22].…”

Section: Introductionmentioning

confidence: 99%

“…Overexpression of this hybrid results in a three-fold increase in anabolism of PGI 2 in cell lines and shows an increased ability to efficiently convert AA into PGI 2 [22]. CP-TG mice expressing this enzyme express show resistance to induced thrombotic stroke and cardiac arrest [21]. Our aim in this study was to investigate whether PGI 2 could beneficially affect cognitive-like behaviors in PGIS-overexpressing mice.…”

Section: Introductionmentioning

confidence: 99%

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Elevated prostacyclin biosynthesis in mice impacts memory and anxiety-like behavior

Vollert

Ohia

Akasaka

et al. 2014

Behavioural Brain Research

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Prostacyclin is an endogenous lipid metabolite with properties of vasodilation and anti-platelet aggregation. While the effects of prostacyclin on the vascular protection have been well-documented, the role of this eicosanoid in the central nervous system has not been extensively studied. Recently, a transgenic mouse containing a hybrid enzyme, of cyclooxygenase-1 linked to prostacyclin synthase, was developed that produces elevated levels of prostacyclin in vivo. The goal of this study was to investigate whether increased prostacyclin biosynthesis could affect behavioral phenotypes in mice. Our results uncovered that elevated levels of prostacyclin broadly affect both cognitive and non-cognitive behaviors, including decreased anxiety-like behavior and improved learning in the fear-conditioning memory test. This study demonstrates that prostacyclin plays an important, but previously unrecognized, role in central nervous system function and behavior.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Elevated prostacyclin biosynthesis in mice impacts memory and anxiety-like behavior

Vollert

Ohia

Akasaka

et al. 2014

Behavioural Brain Research

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“…They showed high expression levels of the active hybrid enzyme with triple catalytic activities (converting AA into PGG 2 , then PGH 2 and finally into active PGI 2 ), which resulted in redirecting the conversion of endogenous AA metabolites more toward the favorable PGI 2 production rather than the unfavorable TXA 2 and PGE 2 production 11 – 13 . These in vitro molecular and cellular studies, and preliminary experiments 15 have provided a basis for us to hypothesize that the single gene of the hybrid enzyme could reduce the risk of heart disease in vivo . In this study, we integrated the protein engineering, enzyme complex construction, and transgenic mouse technique to gain primary control of cellular AA metabolism in favor of PGI 2 biosynthesis and to disfavor PGE 2 and TXA 2 biosynthesis in vivo .…”

Section: Introductionmentioning

confidence: 99%

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

Ling

Mohite

Murdoch

et al. 2018

Sci Rep

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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.

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A novel single‐chain enzyme complex with chain reaction properties rapidly producing thromboxane A₂ and exhibiting powerful anti‐bleeding functions

Ling

et al. 2019

J Cellular Molecular Medi

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Uncontrollable bleeding is still a worldwide killer. In this study, we aimed to investigate a novel approach to exhibit effective haemostatic properties, which could possibly save lives in various bleeding emergencies. According to the structure‐based enzymatic design, we have engineered a novel single‐chain hybrid enzyme complex (SCHEC), COX‐1‐10aa‐TXAS. We linked the C‐terminus of cyclooxygenase‐1 (COX‐1) to the N‐terminus of the thromboxane A2 (TXA2) synthase (TXAS), through a 10‐amino acid residue linker. This recombinant COX‐1‐10aa‐TXAS can effectively pass COX‐1–derived intermediate prostaglandin (PG) H2 (PGH2) to the active site of TXAS, resulting in an effective chain reaction property to produce the haemostatic prostanoid, TXA2, rapidly. Advantageously, COX‐1‐10aa‐TXAS constrains the production of other pro‐bleeding prostanoids, such as prostacyclin (PGI2) and prostaglandin E2 (PGE2), through reducing the common substrate, PGH2 being passed to synthases which produce aforementioned prostanoids. Therefore, based on these multiple properties, this novel COX‐1‐10aa‐TXAS indicated a powerful anti‐bleeding ability, which could be used to treat a variety of bleeding situations and could even be useful for bleeding prone situations, including nonsteroidal anti‐inflammatory drugs (NSAIDs)‐resulted TXA2‐deficient and PGI2‐mediated bleeding disorders. This novel SCHEC has a great potential to be developed into a biological haemostatic agent to treat severe haemorrhage emergencies, which will prevent the complications of blood loss and save lives.

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Resistant to thrombosis, induced stroke and heart arrest by incorporation of a single gene of PGI2-synthesizing COX-1-PGIS in vivo: Implication against human heart disease

Cited by 5 publications

References 10 publications

Elevated prostacyclin biosynthesis in mice impacts memory and anxiety-like behavior

Elevated prostacyclin biosynthesis in mice impacts memory and anxiety-like behavior

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

A novel single‐chain enzyme complex with chain reaction properties rapidly producing thromboxane A₂ and exhibiting powerful anti‐bleeding functions

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Resistant to thrombosis, induced stroke and heart arrest by incorporation of a single gene of PGI2-synthesizing COX-1-PGIS in vivo: Implication against human heart disease

Cited by 5 publications

References 10 publications

Elevated prostacyclin biosynthesis in mice impacts memory and anxiety-like behavior

Elevated prostacyclin biosynthesis in mice impacts memory and anxiety-like behavior

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

A novel single‐chain enzyme complex with chain reaction properties rapidly producing thromboxane A2 and exhibiting powerful anti‐bleeding functions

Contact Info

Product

Resources

About

A novel single‐chain enzyme complex with chain reaction properties rapidly producing thromboxane A₂ and exhibiting powerful anti‐bleeding functions