TRPC6 counteracts TRPC3-Nox2 protein complex leading to attenuation of hyperglycemia-induced heart failure in mice
Year: 2017
Type: article
Abstract: Excess production of reactive oxygen species (ROS) caused by hyperglycemia is a major risk factor for heart failure. We previously reported that transient receptor potential canonical 3 (TRPC3) channel mediates pressure overload-induced maladaptive cardiac fibrosis by forming stably functional complex with NADPH oxidase 2 (Nox2). Although TRPC3 has been long suggested to form hetero-multimer channels with TRPC6 and function as diacylglycerol-activated cation channels coordinately, the role of TRPC6 in heart is still obscure. We 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.
Source: Scientific Reports
Institutions: National Institutes of Natural Sciences, The Graduate University for Advanced Studies, SOKENDAI, Okazaki Institute for Integrative Bioscience, National Institute for Physiological Sciences, Kyushu University, University of Tsukuba, EA Pharma (Japan), Ajinomoto (Japan), National Institutes of Health, Pontificia Universidad Católica Argentina, National Institute of Environmental Health Sciences, Japan Science and Technology Agency
Language: English
Topic: Ion Channels and Receptors
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
Awards: Transmembrane Signaling Mechanisms Involving TRP Channels, Adaptation to Environmental stress and quality control of myocardial mitochondria by reactive sulfur species, Cardiovascular protective effect by adaptation and maintenance in response to continuous exercise training, Comprehensive study on environmental electrophiles-mediated signal transduction pathways regulated by reactive sulfur species, G6034523203, Study on the regulation of cardiac homeostasis by formation of TRPC3/6 channel protein complex, A novel model for causing senescence via mitochondrial dysfunction by environmental factors, Elucidation of molecualr mechanism underlying maintenance of living body homeostasis by mechano-activated molecules and establishment of a strategy for exercise-mimetic drug development
OpenAlex ID: W2739893199