| First Author | Scruggs SB | Year | 2006 |
| Journal | J Mol Cell Cardiol | Volume | 40 |
| Issue | 4 | Pages | 465-73 |
| PubMed ID | 16445938 | Mgi Jnum | J:108886 |
| Mgi Id | MGI:3625235 | Doi | 10.1016/j.yjmcc.2005.12.009 |
| Citation | Scruggs SB, et al. (2006) Partial replacement of cardiac troponin I with a non-phosphorylatable mutant at serines 43/45 attenuates the contractile dysfunction associated with PKCepsilon phosphorylation. J Mol Cell Cardiol 40(4):465-73 |
| abstractText | We have previously reported a transgenic mouse that over-expresses constitutively active PKCepsilon in the myocardium and exhibits a steady progression to heart failure. Associated with the decline in function was an increased phosphorylation of sarcomeric proteins including cardiac troponin I (cTnI). To determine whether PKCepsilon phosphorylation of cTnI is sufficient to induce cardiac maladaptation, we have generated a double transgenic mouse (DbTG) that expresses constitutively active PKCepsilon and cTnI harboring non-phosphorylatable mutations in the putative PKC phosphorylation sites (S43A, S45A). We compared the hemodynamic and biochemical properties of the hearts from the DbTG mice to the non-transgenic and single transgenic lines at both 3 and 12 months of age. While no significant differences in LV function were noted in 3-month groups, the depression of function in the PKCepsilon mice was attenuated in the double transgenic mice at 12 months. The improvement in cardiac function was correlated with decreased beta-myosin heavy chain and ANF mRNA expression in the 12m DbTG mice. The extent of cTnI phosphorylation was determined using a novel one-dimensional, non-equilibrium isoelectric focusing technique. At 3 months the migration of cTnI phospho-species was different in the PKCepsilon mice and to a lesser degree in the DbTG compared to all other groups. At 12 months additional phospho-species were observed in both the PKCepsilon and DbTG samples, along with an overall shift in the distribution of phospho-species in all groups due to age. These results suggest that phosphorylation of cTnI by PKCepsilon is associated with contractile dysfunction and partial replacement of serines 43/45 improves cardiac performance. Therefore, we conclude that phosphorylation of cTnI at Ser 43 and 45 may contribute to the progression of failure. |
