Propranolol prevents the development of heart failure by restoring FKBP12. 6-mediated stabilization of ryanodine receptor

M Doi, M Yano, S Kobayashi, M Kohno, T Tokuhisa… - Circulation, 2002 - Am Heart Assoc
M Doi, M Yano, S Kobayashi, M Kohno, T Tokuhisa, S Okuda, M Suetsugu, Y Hisamatsu…
Circulation, 2002Am Heart Assoc
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 β-blockers can correct this defect in
RyR in tachycardia-induced heart failure and thereby improve cardiac function. Methods and
Results—SRs were isolated from dog left ventricular muscles (normal group, 4 weeks of …
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 β-blockers can correct this defect in RyR in tachycardia-induced heart failure and thereby improve cardiac function.
Methods and 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.
Am Heart Assoc