title: Angiotensin II type 1 receptor blockade prevents diastolic heart failure through modulation of Ca(2+) regulatory proteins and extracellular matrix.
abstract: BACKGROUND
  Angiotensin II type 1 receptor (AT(1)R) blockade attenuates left ventricular relaxation abnormality and myocardial stiffening in a model of hypertensive diastolic heart failure, but the mechanisms remain unclear.
  
  
  OBJECTIVE
  To test the hypothesis that such benefits are provided by modulation of the quantitative or qualitative changes, or both, in Ca2+ regulatory proteins and extracellular matrix.
  
  
  METHODS
  Dahl salt-sensitive rats fed a diet containing 8% sodium chloride from 7 weeks of age present pulmonary congestion as a result of diastolic dysfunction with preserved systolic function, around 20 weeks of age. In this study, animals of this model were divided into groups that received (n = 7) or did not receive (n = 6) a subdepressor dose of an AT(1)R antagonist (candesartan cilexetil) from 8 weeks of age.
  
  
  RESULTS
  Long-term AT(1)R blockade prevented the development of diastolic heart failure through attenuation of left ventricular relaxation abnormality and myocardial stiffening without a reduction in blood pressure. Left ventricular relaxation abnormality was not associated with any change in the ratio of abundance of phospholamban to that of sarcoplasmic reticulum Ca2+-ATPase 2a protein, but was accompanied by a decrease in Ser16-phosphorylated phospholamban. The AT(1)R blockade inhibited this decrease. Attenuation in myocardial stiffening was associated with reduced tissue collagen content, attenuated collagen cross-linking, and suppressed gene expression of collagen type I rather than type III.
  
  
  CONCLUSIONS
  AT(1)R blockade prevented abnormal relaxation at least partly through functional alterations in Ca2+-handling proteins in a hypertensive model of diastolic heart failure. It attenuated myocardial stiffening through preventing a shift in the phenotype of collagen synthesized and the accumulation of cross-linked collagen. These beneficial effects of AT(1)R blockade in diastolic heart failure are achieved without a reduction in blood pressure.
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Mano
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Nishikawa
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Michihiko
authors.initials: M
authors.lastname: Tada
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miwa
authors.forename: Tohru
authors.initials: T
authors.lastname: Masuyama
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003971:Diastole / Q000187:drug effects / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D015870:Gene Expression; D006333:Heart Failure / Q000378:metabolism / Q000517:prevention & control*; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D010766:Phosphorylation; D051381:Rats; D020303:Rats, Inbred Dahl; D044140:Receptor, Angiotensin, Type 1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013777:Tetrazoles; D000099211:Phospholamban
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D003094:Collagen; D003432:Cross-Linking Reagents; D000242:Cyclic AMP; D044140:Receptor, Angiotensin, Type 1; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013777:Tetrazoles; D000099211:Phospholamban; C077793:candesartan cilexetil