title: Blockade of sarcolemmal TRPV2 accumulation inhibits progression of dilated cardiomyopathy.
abstract: OBJECTIVE
  Dilated cardiomyopathy (DCM) is a severe disorder defined by ventricular dilation and contractile dysfunction. Abnormal Ca(2+) handling is hypothesized to play a critical pathological role in DCM progression. The transient receptor potential vanilloid 2 (TRPV2) has been previously suggested as a candidate pathway for enhanced Ca(2+) entry. Here, we examined the sarcolemmal accumulation of TRPV2 in various heart-failure model animals and DCM patients, and assessed whether presently available inhibitory tools against TRPV2 ameliorate DCM symptoms.
  
  
  RESULTS
  Immunological and cell physiological analyses revealed that TRPV2 is highly concentrated and activated in the ventricular sarcolemma of DCM patients and three animal models-δ-sarcoglycan-deficient hamsters (J2N-k), transgenic mice over-expressing sialytransferase (4C30), and doxorubicin (DOX)-induced DCM mice. Over-expression of the amino-terminal (NT) domain of TRPV2 could block the plasma membrane accumulation and influx of Ca(2+) via TRPV2. Transgenic (Tg) or adenoviral expression of the NT domain in DCM animals caused effective removal of sarcolemmal TRPV2 along with reduction in the phosphorylation of calmodulin-dependent protein kinase II (CaMKII) and reactive oxygen species (ROS) production, which were activated in DCM; further, it prevented ventricular dilation and fibrosis, ameliorated contractile dysfunction in DCM, and improved survival of the affected animals. The TRPV2 inhibitor tranilast markedly suppressed DCM progression.
  
  
  CONCLUSIONS
  Sarcolemmal TRPV2 accumulation appears to have considerable pathological impact on DCM progression, and blockade of this channel may be a promising therapeutic strategy for treating advanced heart failure.
authors.affiliation: Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan. yukoiwat@ri.ncvc.go.jp
authors.forename: Yuko
authors.initials: Y
authors.lastname: Iwata
authors.forename: Hitomi
authors.initials: H
authors.lastname: Ohtake
authors.forename: Osamu
authors.initials: O
authors.lastname: Suzuki
authors.forename: Junichiro
authors.initials: J
authors.lastname: Matsuda
authors.forename: Kazuo
authors.initials: K
authors.lastname: Komamura
authors.forename: Shigeo
authors.initials: S
authors.lastname: Wakabayashi
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000517:prevention & control; D006224:Cricetinae; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012508:Sarcolemma / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000502:physiology*; D062367:ortho-Aminobenzoates / Q000494:pharmacology
chemical_list: D001896:Boron Compounds; D015220:Calcium Channels; D050916:TRPV Cation Channels; C400769:TRPV2 protein, human; C485717:Trpv2 protein, mouse; D062367:ortho-Aminobenzoates; C109986:2-aminoethoxydiphenyl borate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C012293:tranilast; D002118:Calcium
keywords: Ca2+-permeable channel; DOX-induced cardiomyopathy; Dilated cardiomyopathy; Heart failure; Therapeutic tool