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TRPC6 counteracts TRPC3-Nox2 protein complex leading to attenuation of hyperglycemia-induced heart failure in mice
Sayaka Oda1,2, Takuro Numaga-Tomita1,2, Naoyuki Kitajima1,3
1Division of Cardiocirculatory Signaling, National Institute for Physiological Sciences (Okazaki Institute for Integrative Bioscience), National Institutes of Natural Sciences, Aichi, 444-8787, Japan.
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.
Insights
Transient Receptor Potential Canonical 3 (TRPC3) channels protect against heart failure. TRPC3 disruption by TRPC6 loss attenuates hyperglycemia-induced heart failure by destabilizing NADPH oxidase 2 (Nox2) complexes.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Oxidative Stress Research
Background:
- Hyperglycemia-induced reactive oxygen species (ROS) are a major heart failure risk factor.
- Transient Receptor Potential Canonical 3 (TRPC3) channels, complexed with NADPH oxidase 2 (Nox2), mediate pressure overload-induced cardiac fibrosis.
- The role of TRPC6 in cardiac function and heart failure remains largely unknown.
Purpose of the Study:
- To investigate the role of TRPC6 in pressure overload-induced heart failure.
- To elucidate the mechanism by which TRPC6 influences cardiac function, particularly in the context of hyperglycemia and oxidative stress.
- To determine the relationship between TRPC3, TRPC6, and Nox2 in cardiac pathophysiology.
Main Methods:
- Utilized TRPC6-deficient mice subjected to transverse aortic constriction (TAC) to model pressure overload.
- Administered streptozotocin to TRPC6-deficient mice to induce hyperglycemia and assess cardiac function.
- Performed gene expression analysis, ROS production assays, and cytokine profiling in cardiac tissues.
- Investigated protein-protein interactions between TRPC6, TRPC3, and Nox2 using molecular biology techniques.
- Examined cytokine expression in rat cardiomyocytes following TRPC6 knockdown.
Main Results:
- TRPC6 deficiency did not affect pressure overload-induced heart failure but reduced interstitial fibrosis.
- TRPC6-deficient hearts showed increased inflammatory cytokine induction post-TAC.
- Hyperglycemia exacerbated cardiac dysfunction and lipid peroxidation in TRPC6-deficient mice compared to wild-type and TRPC3-deficient mice.
- TRPC6 knockdown increased basal cytokine expression in cardiomyocytes.
- TRPC6 interacts with Nox2, but its abundance is inversely correlated with Nox2 levels.
Conclusions:
- TRPC6 plays a complex role in cardiac response to stress, distinct from its interaction with TRPC3.
- TRPC6 deficiency exacerbates hyperglycemia-induced cardiac dysfunction, potentially via altered inflammatory responses and lipid peroxidation.
- TRPC6 appears to destabilize the TRPC3-Nox2 complex, suggesting a mechanism for attenuating hyperglycemia-induced heart failure.
