| First Author | Najafi A | Year | 2016 |
| Journal | Cardiovasc Res | Volume | 110 |
| Issue | 2 | Pages | 200-14 |
| PubMed ID | 26825555 | Mgi Jnum | J:252580 |
| Mgi Id | MGI:6107389 | Doi | 10.1093/cvr/cvw026 |
| Citation | Najafi A, et al. (2016) Selective phosphorylation of PKA targets after beta-adrenergic receptor stimulation impairs myofilament function in Mybpc3-targeted HCM mouse model. Cardiovasc Res 110(2):200-14 |
| abstractText | AIMS: Hypertrophic cardiomyopathy (HCM) has been associated with reduced beta-adrenergic receptor (beta-AR) signalling, leading downstream to a low protein kinase A (PKA)-mediated phosphorylation. It remained undefined whether all PKA targets will be affected similarly by diminished beta-AR signalling in HCM. We aimed to investigate the role of beta-AR signalling on regulating myofilament and calcium handling in an HCM mouse model harbouring a gene mutation (G > A transition on the last nucleotide of exon 6) in Mybpc3 encoding cardiac myosin-binding protein C. METHODS AND RESULTS: Cardiomyocyte contractile properties and phosphorylation state were measured in left ventricular permeabilized and intact cardiomyocytes isolated from heterozygous (HET) or homozygous (KI) Mybpc3-targeted knock-in mice. Significantly higher myofilament Ca(2)(+)sensitivity and passive tension were detected in KI mice, which were normalized after PKA treatment. Loaded intact cardiomyocyte force-sarcomere length relation was impaired in both HET and KI mice, suggesting a reduced length-dependent activation. Unloaded cardiomyocyte function revealed an impaired myofilament contractile response to isoprenaline (ISO) in KI, whereas the calcium-handling response to ISO was maintained. This disparity was explained by an attenuated increase in cardiac troponin I (cTnI) phosphorylation in KI, whereas the increase in phospholamban (PLN) phosphorylation was maintained to wild-type values. CONCLUSION: These data provide evidence that in the KI HCM mouse model, beta-AR stimulation leads to preferential PKA phosphorylation of PLN over cTnI, resulting in an impaired inotropic and lusitropic response. |
