Cardiotrophin-1 (CT-1) was discovered by Pennica et al. in 1995 in mouse cardiac embryonic stem cells and was named cardiotrophin because of its ability to promote cardiomyocyte hypertrophy in vitro. CT-1 is stable in ethylenediaminetetraacetic acid (EDTA)-treated whole blood specimens, and can be stored for 48 hours at room temperature or at low temperature. In recent years, CT-1 has been found to be a substance with regulatory functions in various organs and diseases.
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Introduction of Cardiotrophin-1
CT-1 is a protein with a molecular weight of 21.5 kD. Based on the similarity of its amino acid sequence, CT-1 is classified as a member of the interleukin-6 family. Some members of this family often play pathological roles as signaling stimuli for the transmembrane protein gp130. The messenger ribonucleic acid (mRNA) of CT-1 is expressed in the mouse heart and other tissues, with a length of 1.4 kb. In humans, the mRNA length of CT-1 is 1.7 kb, and it is expressed in adult heart, skeletal muscle, ovaries, colon, prostate, testes, as well as in the kidneys and lungs of fetuses. Additionally, CT-1 can be synthesized and secreted by vascular endothelial cells and adipocytes.
The gene encoding CT-1 consists of 3 exons and is located in the chromosomal region 16p11.1~16p11.2 in humans. The various biological functions of CT-1 are mainly realized through binding to the transmembrane receptor composed of leukemia inhibitory factor receptor (LIFR β) and gp130. Research has confirmed that CT-1 mediates and utilizes tyrosine kinases such as Janus kinase 1/2 and tyrosine kinase (Tyk) 2, followed by signal transduction through the activation of transcription factor-3 (STAT-3) and mitogen-activated protein kinase (MAPK) family extracellular signal-regulated kinase 1/2 pathways.
Biological Functions of Cardiotrophin-1 (CT-1)
CT-1 is predominantly synthesized by both myocardial and non-myocardial cells within the heart. It is then released into the peripheral circulation via the coronary venous sinus. CT-1 demonstrates the capacity to induce hypertrophy not only in myocardial cells but also in skeletal and smooth muscle cells. Beyond this, it serves protective functions for myocardial, neuronal, and liver cells, participating in a range of roles, including safeguarding myocardial health, preparing for cardiac pathological conditions, influencing hemodynamics, and contributing to endocrine functions.
Studies have indicated that in pathological conditions such as genetic hypertension, coronary artery disease, myocardial infarction, dilated cardiomyopathy, heart failure, valve disease, and hypoxia, excessive expression of CT-1 can be observed. Furthermore, CT-1 also plays a role in the liver and adipose tissue. Recent research has shown a significant increase in CT-1 concentration in the plasma of patients with metabolic syndrome, possibly related to the overexpression in adipose tissue. There is also evidence suggesting that CT-1 plays a crucial role in energy metabolism. Mice lacking CT-1 exhibit disruptions in energy expenditure and develop adult-onset obesity, hypercholesterolemia, and type 2 diabetes, similar to human metabolic syndrome. In congenital or acquired obesity animal models, recombinant CT-1 has been observed to treat obesity and related diabetes by increasing energy expenditure and reducing food intake.
The Relationship between CT-1 and Cardiovascular Disease
CT-1 is intricately involved in the pathophysiology of various cardiovascular diseases, extending beyond being a mere biomarker. Its association with the progression of cardiovascular diseases, such as hypertension, cardiac hypertrophy, and heart failure, underscores its complex role in cardiac pathology. Elevated CT-1 levels are commonly observed in cardiovascular conditions, including hypertension, valve diseases, congestive heart failure, and coronary artery disease. Studies suggest a correlation between CT-1 and congenital heart diseases, particularly those related to hypoxia.
In hypertensive heart disease, CT-1 levels are elevated, likely due to increased pressure load on the left ventricle. CT-1 also shows relevance in valve diseases, where its increased levels are associated with severe mitral valve insufficiency. Additionally, CT-1 is implicated in congestive heart failure, with elevated levels correlating with the severity of heart failure. In the context of coronary artery disease, CT-1 plays a crucial role in promoting inflammation, foam cell formation, and atherosclerotic plaque development.
Furthermore, CT-1 is involved in the early stages of trauma repair after myocardial infarction, promoting cell survival, hypertrophy of remaining myocardial cells, and fibroblast proliferation and migration. In the chronic phase post-myocardial infarction, CT-1 may contribute to pathological ventricular hypertrophy, leading to ventricular dilation and functional degradation. Overall, CT-1 emerges as a multifaceted player in cardiovascular diseases, influencing their development and progression at various stages.
References
- Pennica D.; et al. Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proceedings of the National Academy of Sciences. 1995, 92(4): 1142-1146.
- Calabro P.; et al. Novel insights into the role of cardiotrophin-1 in cardiovascular diseases. Journal of Molecular and Cellular Cardiology. 2009, 46(2): 142-148.
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