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release date:2017.08.23

TRPC6 counteracts TRPC3-Nox2 protein complex leading to attenuation of hyperglycemia-induced heart failure in mice

Research Results Medicine/Dentistry/Pharmaceutical Sciences

The research groups led by Professor Nishida of Kyushu University, here demonstrated that deletion of TRPC6 had no impact on pressure overload-induced heart failure despite inhibiting interstitial fibrosis in mice. TRPC6-deficient mouse hearts 1 week after transverse aortic constriction showed comparable increases in fibrotic gene expressions and ROS production but promoted inductions of inflammatory cytokines, compared to wild type hearts. Treatment of TRPC6-deficient mice with streptozotocin caused severe reduction of cardiac contractility with enhancing urinary and cardiac lipid peroxide levels, compared to wild type and TRPC3-deficient mice. Knockdown of TRPC6, but not TRPC3, enhanced basal expression levels of cytokines in rat cardiomyocytes. TRPC6 could interact with Nox2, but the abundance of TRPC6 was inversely correlated with that of Nox2. These results strongly suggest that Nox2 destabilization through disrupting TRPC3-Nox2 complex underlies attenuation of hyperglycemia-induced heart failure by TRPC6.
This research achievement was published online in Scientific Reports on August 8, 2017, 18.

Previous finding: TRPC3 positively regulates reactive oxygen species during maladaptive cardiac stiffness (fibrosis) in mice.

[Ref.]
Kitajima N. et al., TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling. Sci. Rep. 6, 37001; doi: 10.1038/srep37001 (2016).
Numaga-Tomita, T. et al., TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis. Sci. Rep. 6, 39383; doi: 10.1038/srep39383 (2016).

Deletion of TRPC6 but not TRPC3 promotes streptozotocin-induced cardiac dysfunction in mice.

Schema of negative crosstalk between TRPC6 and TRPC3-Nox2 complex in cardiomyocytes.

In resting condition, TRPC3 and TRPC6 channels function independently or coordinately in cardiomyocytes. Once hearts are exposed to environmental stresses such as hemodynamic load and hyperglycemia, TRPC3 forms stable protein complex with Nox2, which evokes aberrant ROS production in cardiomyocytes. In contrast, environmental stresses also upregulate TRPC6, which can counteract formation of the TRPC3-Nox2 complex in cardiomyocytes, leading to Nox2 destabilization, and resulting in negative regulation of ROS signaling in heart.

Research-related inquiries

Motohiro Nishida, Professor, Faculty of Pharmaceutical Sciences
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