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Published on: February 25, 2016
Dysfunctional nitric oxide signalling increases risk of myocardial infarction
Jeanette Erdmann1, Klaus Stark2, Ulrike B Esslinger3
11] Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany [3].
Insights
Genetic mutations in GUCY1A3 and CCT7 impair nitric oxide signaling, increasing myocardial infarction risk through accelerated thrombus formation. This discovery offers a potential new therapeutic target for heart attack prevention.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Thrombosis Research
Background:
- Myocardial infarction (MI) is a leading cause of death, often caused by atherosclerotic plaque rupture and subsequent thrombus formation.
- Genetic predisposition plays a significant role in MI, highlighted by family history.
- Next-generation sequencing has advanced the identification of genetic mutations linked to diseases.
Purpose of the Study:
- To investigate the genetic basis of myocardial infarction in a family with a strong history of the condition.
- To identify and characterize novel mutations in genes related to nitric oxide signaling and soluble guanylyl cyclase function.
- To explore the functional consequences of identified mutations on cardiovascular health and thrombus formation.
Main Methods:
- Segregation analysis of two heterozygous mutations in GUCY1A3 and CCT7 within an extended MI family.
- In vitro studies to assess the impact of mutations on soluble guanylyl cyclase (sGC) protein content and activity.
- Analysis of platelet function and cGMP formation in mutation carriers.
- In vivo studies using mice deficient in α1-sGC to evaluate thrombus formation.
Main Results:
- Identified two private, heterozygous mutations in GUCY1A3 and CCT7 segregating in an MI family.
- Demonstrated that these mutations severely reduce α1-sGC and β1-sGC protein levels and impair sGC activity.
- Observed reduced sGC protein and impaired nitric oxide-induced cGMP formation in platelets of digenic mutation carriers.
- Showed accelerated thrombus formation in α1-sGC deficient mice.
Conclusions:
- Established a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signaling and increased myocardial infarction risk.
- Hypothesized that accelerated thrombus formation is a key mechanism underlying this increased risk.
- Proposed that correcting this signaling defect could be a novel therapeutic strategy for MI prevention.
Abstract:
Myocardial infarction, a leading cause of death in the Western world, usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery. The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history. Next-generation sequencing in families with several affected individuals has revolutionized mutation identification. Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the α1 subunit of soluble guanylyl cyclase (α1-sGC), and CCT7 encodes CCTη, a member of the tailless complex polypeptide 1 ring complex, which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation. We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce α1-sGC as well as β1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in α1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.
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