Cardiotrophin-1 increases angiotensinogen mRNA in rat cardiac myocytes through STAT3 : an autocrine loop for...

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cytokine Signaling

Background:

• Cardiotrophin-1 (CT-1) is an interleukin-6-related cytokine known to induce cardiac myocyte hypertrophy.
• The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is a key signaling cascade involved in cellular responses.

Purpose of the Study:

• To investigate the role of the local renin-angiotensin system (RAS) in CT-1-induced cardiac myocyte hypertrophy.
• To elucidate the specific mechanisms by which CT-1 upregulates the RAS via the JAK/STAT pathway.

Main Methods:

• Assessed angiotensinogen mRNA expression in cardiac myocytes following CT-1 treatment.
• Utilized transient transfection assays to examine angiotensinogen gene promoter activity.
• Employed a specific Janus kinase 2 (JAK2) inhibitor (AG490) and a mutated angiotensinogen promoter.
• Tested the effect of an angiotensin II type 1 receptor antagonist (losartan) on CT-1-induced hypertrophy.

Main Results:

• CT-1 increased angiotensinogen mRNA expression through STAT3 activation.
• STAT3 homodimer binding to the angiotensinogen gene promoter's St-domain was induced by CT-1.
• JAK2 inhibition and promoter mutations abolished CT-1-induced promoter activation.
• Losartan significantly attenuated CT-1-induced cardiac myocyte hypertrophy.

Conclusions:

• CT-1 upregulates the local RAS via JAK/STAT signaling, contributing to cardiac myocyte hypertrophy.
• STAT3 activation and subsequent angiotensinogen gene expression are critical mediators.
• This study highlights an interaction between cytokine receptors and G-protein-coupled receptors in cardiac remodeling.