04 February 2019 by Dr. Kurt Prins

Interleukin-6 as a potential modulator of right ventricular function via the microtubule-junctophilin-2-T-tubule pathway

Background:

Pulmonary arterial hypertension (PAH) is a progressive and lethal disease characterized by pulmonary vascular remodeling resulting in right ventricle dysfunction (RVD). Currently, the molecular mediators of RVD in PAH are incompletely understood and thus further exploration is needed to identify molecular targets for future RV-directed therapies. We recently demonstrated microtubule-mediated junctophilin-2 dysregulation promoted t-tubule disruption and resulted in RVD; however the upstream moderators of this pathway have not been delineated. Interleukin-6 (IL6), an inflammatory cytokine that is associated with RVD in PAH patients, stabilizes microtubule via its downstream effector protein signal transducer and activator of transcript 3 (STAT3) in noncardiac cells. However, the effects of IL6 on microtubules in cardiomyocytes are less well described.

Methods:

Control ventricular cardiomyocytes were isolated and cultured in the presence of IL6 or phosphate buffered saline. Confocal microscopy examined the effects of IL6 on microtubule density, junctophilin-2 localization, and t-tubule organization. Immunoblots were performed on control and monocrotaline (MCT) rats cardiac extracts to examine IL6 pathway activation.

Results:

In isolated cardiomyocytes, IL6 promoted microtubule stabilization, junctophilin-2 redistribution, and adverse t-tubule remodeling. Western blot analysis revealed an increase in the IL6 receptor GP130 (1.4±0.1 arbitrary units (AU), STAT3 (3.1±0.4 AU) and phosphorylated STAT3, the activated form of STAT3, (12.2±2.7 AU) in the MCT RV. α-tubulin (2.9±0.2 AU) and β-tubulin (2.2±0.1 AU), the individual subunits of microtubules, were also elevated in the RV. Conversely, in the MCT LV GP130 (0.7±0.4 AU), STAT3 (0.7±0.1 AU), phosphorylated STAT3 (0.9±0.8 AU), α-tubulin (0.9±0.07 AU), and β-tubulin (0.8±0.07 AU) were either downregulated or unchanged.

Conclusion:

IL6 promotes microtubule-mediated t-tubule remodeling. IL6 signaling is activated in a RV-specific pattern in MCT rats which is associated with microtubule stabilization. These results identify a potential mechanism linking elevated levels of IL6 to RVD in PAH that will require further exploration.

table 98.PNG

Key Contributors

Lauren Rose, BS 1, Lian Tian, PhD 2, Danchen Wu, MD, PhD 2, Thenappan Thenappan, MD 1, Stephen L Archer, MD 2, and Kurt Prins, MD, PhD 1 : 1. Cardiovascular Division, University of Minnesota, Minneapolis, MN 2. Department of Medicine, Queen’s University, Kingston, ON


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