Propranolol prevents the development of heart failure by restoring FKBP12.6-mediated stabilization of ryanodine receptor.
BACKGROUND
In heart failure, protein kinase A-mediated hyperphosphorylation of ryanodine receptors (RyRs) in sarcoplasmic reticulum (SR) causes dissociation of FKBP12.6 from RyRs. This results in an abnormal Ca2+ leak through RyRs, possibly leading to cardiac dysfunction. In the present study, we assess whether beta-blockers can correct this defect in RyR in tachycardia-induced heart failure and thereby improve cardiac function.


RESULTS
SRs were isolated from dog left ventricular muscles (normal group, 4 weeks of rapid right ventricular pacing with or without propranolol [P(+) or P(-)]). End-diastolic and end-systolic diameters both increased less in P(+) than P(-), associated with a smaller decrease in fractional shortening in P(+). In SR from P(-), a prominent Ca2+ leak was observed, and FK506 (which dissociates FKBP12.6 from RyR) did not induce an additional Ca2+ leak. However, there was no appreciable Ca2+ leak in SR from P(+), although FK506 induced a Ca2+ leak as in normal SRs. In SR from P(+), an FK506-induced conformational change in RyR, which was virtually absent in SR from P(-), was observed as in normal SRs. Both the stoichiometry of FKBP12.6 versus RyR, assessed by [3H]FK506 and [3H]ryanodine binding assays, and the protein expression of FKBP12.6, assessed by Western blot analysis, were restored by propranolol toward the levels seen in normal SRs.


CONCLUSIONS
Low-dose propranolol corrects the defective interaction of FKBP12.6 with RyR (restoration of RyR conformational change and prevention of Ca2+ leak from RyR), apparently resulting in an attenuation of intracellular Ca2+ overload and hence preventing the development of left ventricular remodeling in heart failure.
Doi
Masahiro
M
Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University School of Medicine, Yamaguchi, Japan.
Yano
Masafumi
M
Kobayashi
Shigeki
S
Kohno
Masateru
M
Tokuhisa
Takahiro
T
Okuda
Shinichi
S
Suetsugu
Masae
M
Hisamatsu
Yuhji
Y
Ohkusa
Tomoko
T
Kohno
Michihiro
M
Matsuzaki
Masunori
M
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D003971:Diastole / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D006333:Heart Failure / Q000503:physiopathology* / Q000517:prevention & control*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011433:Propranolol / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013599:Systole / Q000187:drug effects; D016559:Tacrolimus / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D019837:Ryanodine Receptor Calcium Release Channel; D011433:Propranolol; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D002118:Calcium; D016559:Tacrolimus