TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis.

Abstract

Structural cardiac remodeling, accompanying cytoskeletal reorganization of cardiac cells, is a major clinical outcome of diastolic heart failure. A highly local Ca2+ influx across the plasma membrane has been suggested to code signals to induce Rho GTPase-mediated fibrosis, but it is obscure how the heart specifically decodes the local Ca2+ influx as a cytoskeletal reorganizing signal under the conditions of the rhythmic Ca2+ handling required for pump function. We found that an inhibition of transient receptor potential canonical 3 (TRPC3) channel activity exhibited resistance to Rho-mediated maladaptive fibrosis in pressure-overloaded mouse hearts. Proteomic analysis revealed that microtubule-associated Rho guanine nucleotide exchange factor, GEF-H1, participates in TRPC3-mediated RhoA activation induced by mechanical stress in cardiomyocytes and transforming growth factor (TGF) β stimulation in cardiac fibroblasts. We previously revealed that TRPC3 functionally interacts with microtubule-associated NADPH oxidase (Nox) 2, and inhibition of Nox2 attenuated mechanical stretch-induced GEF-H1 activation in cardiomyocytes. Finally, pharmacological TRPC3 inhibition significantly suppressed fibrotic responses in human cardiomyocytes and cardiac fibroblasts. These results strongly suggest that microtubule-localized TRPC3-GEF-H1 axis mediates fibrotic responses commonly in cardiac myocytes and fibroblasts induced by physico-chemical stimulation.

• Authors: Takuro Numaga-Tomita, Naoyuki Kitajima, Takuya Kuroda, Akiyuki Nishimura, Kei Miyano, Satoshi Yasuda, Koichiro Kuwahara, Yoji Sato, Tomomi Ide, Lutz Birnbaumer, Hideki Sumimoto, Yasuo Mori, Motohiro Nishida
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 39383 (12 19 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27991560 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Rho Guanine Nucleotide Exchange Factors
• TRPC Cation Channels
• TRPC3 cation channel
• Transforming Growth Factor beta
• NADPH Oxidases
• rhoA GTP-Binding Protein

Topics

• Animals
• Cells, Cultured
• Fibroblasts (metabolism)
• Fibrosis (metabolism)
• Heart (physiology)
• Humans
• Male
• Mice
• Microtubules (metabolism)
• Myocytes, Cardiac (metabolism)
• NADPH Oxidases (metabolism)
• Proteomics (methods)
• Rats
• Rho Guanine Nucleotide Exchange Factors (metabolism)
• Signal Transduction (physiology)
• TRPC Cation Channels (metabolism)
• Transforming Growth Factor beta (metabolism)
• rhoA GTP-Binding Protein (metabolism)