title: Impairment of Excitation-Contraction Coupling in Right Ventricular Hypertrophied Muscle with Fibrosis Induced by Pulmonary Artery Banding.
abstract: Interstitial myocardial fibrosis is one of the factors responsible for dysfunction of the heart. However, how interstitial fibrosis affects cardiac function and excitation-contraction coupling (E-C coupling) has not yet been clarified. We developed an animal model of right ventricular (RV) hypertrophy with fibrosis by pulmonary artery (PA) banding in rats. Two, four, and six weeks after the PA-banding operation, the tension and intracellular Ca2+ concentration of RV papillary muscles were simultaneously measured (n = 33). The PA-banding rats were clearly divided into two groups by the presence or absence of apparent interstitial fibrosis in the papillary muscles: F+ or F- group, respectively. The papillary muscle diameter and size of myocytes were almost identical between F+ and F-, although the RV free wall weight was heavier in F+ than in F-. F+ papillary muscles exhibited higher stiffness, lower active tension, and lower Ca2+ responsiveness compared with Sham and F- papillary muscles. In addition, we found that the time to peak Ca2+ had the highest correlation coefficient to percent of fibrosis among other parameters, such as RV weight and active tension of papillary muscles. The phosphorylation level of troponin I in F+ was significantly higher than that in Sham and F-, which supports the idea of lower Ca2+ responsiveness in F+. We also found that connexin 43 in F+ was sparse and disorganized in the intercalated disk area where interstitial fibrosis strongly developed. In the present study, the RV papillary muscles obtained from the PA-banding rats enabled us to directly investigate the relationship between fibrosis and cardiac dysfunction, the impairment of E-C coupling in particular. Our results suggest that interstitial fibrosis worsens cardiac function due to 1) the decrease in Ca2+ responsiveness and 2) the asynchronous activation of each cardiac myocyte in the fibrotic preparation due to sparse cell-to-cell communication.
authors.affiliation: Department of Cell Physiology, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Yoichiro
authors.identifier: http://orcid.org/0000-0001-7909-2611
authors.initials: Y
authors.lastname: Kusakari
authors.affiliation: Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Urashima
authors.affiliation: Department of Cell Physiology, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Shimura
authors.affiliation: Department of Cell Physiology, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Amemiya
authors.affiliation: Department of Cell Physiology, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Genki
authors.initials: G
authors.lastname: Miyasaka
authors.affiliation: Department of Cell Physiology, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yokota
authors.affiliation: Department of Cell Physiology, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Fujimoto
authors.affiliation: Department of Cell Physiology, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Akaike
authors.affiliation: Department of Cardiac Surgery, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Cell Physiology, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Minamisawa
mesh_terms: D000331:Aequorin / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D002118:Calcium / Q000378:metabolism; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D056966:Excitation Contraction Coupling; D005355:Fibrosis; D015870:Gene Expression; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D008564:Membrane Potentials; D010210:Papillary Muscles / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation; D011651:Pulmonary Artery / Q000503:physiopathology*; D051381:Rats; D019210:Troponin I / Q000378:metabolism
chemical_list: D015415:Biomarkers; D018031:Connexin 43; D019210:Troponin I; D000331:Aequorin; D002118:Calcium