Altered Myocardial Thin-Filament Function in the Failing Dahl Salt-Sensitive Rat Heart

Abstract

Background-Dahl salt-sensitive rats fed a high-salt diet develop compensated left ventricular hypertrophy followed by a transition to myocardial failure. We previously reported an increase in a troponin T isoform (TnT 3 ) and a decrease in TnT phosphorylation in failing Dahl salt-sensitive rat hearts compared with low-salt controls. The present study was undertaken to determine whether the thin filament plays a role in depression of the contractile machinery in this model. Methods and Results-Native thin filaments (NTFs) were isolated intact from rats with compensated left ventricular hypertrophy and failing hearts and compared with age-matched controls. NTF velocity was measured as a function of free calcium in the in vitro motility assay. Maximal velocity was similar in all groups. However, NTFs from failing hearts demonstrated a reduction in calcium sensitivity compared with controls, as reflected in the pCa 50 (5.88Ϯ0.05 versus 6.22Ϯ0.05, respectively, PϽ0.001). No difference in thin-filament motility (pCa 50 , V max ) was observed in rats with compensated left ventricular hypertrophy compared with controls. Protein kinase A treatment of NTFs from control and failing hearts had no effect on thin-filament calcium sensitivity. However, the endothelin receptor blocker bosentan prevented the reduction in thin-filament calcium sensitivity found in failing hearts. Conclusions-The

Augmented Protein Kinase C-α–Induced Myofilament Protein Phosphorylation Contributes to Myofilament Dysfunction in Experimental Congestive Heart Failure

“…4 -10 Moreover, we and others have observed that, in various animal models of end-stage cardiac failure (eg, myocardial infarction, pressure overload) and in different cardiac muscle preparations (eg, cells and trabeculae) isolated from different regions of the myocardium (right versus left ventricle), myofilament function is severely depressed. [11][12][13][14][15][16][17] Furthermore, in a recent report using 2 distinct rat models of ventricular failure, we observed depressed myofilament function secondary to dysfunction of the regulatory cTn complex and increased phosphorylation of cTnI. 11 Our central tenet is that prolonged excess mechanical stress/strain on the myocyte activates several PKC isozymes, a process that, in addition to promoting cell growth and death, also triggers functionally important phosphorylations of several myofilament proteins causing depressed myofilament and, consequently, myocyte function.…”

Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals

“…The DSS model has been reproducibly used to investigate cardiac hypertrophy, diastolic dysfunction, and transition to heart failure (9,16). Therapies shown to attenuate cardiac dysfunction in this model (17,18) ameliorate comparable cardiac abnormalities in humans (19). Importantly, although our retrospective clinical data of activated vitamin D-treated hemodialysis subjects involved small numbers, the observed significant improvement in cardiac alterations is encouraging and suggestive of a potential for clinical intervention.…”

Endothelin receptor blockade has an oxygen-saving effect in Dahl salt-sensitive rats with heart failure

“…We (21) previously reported that Dahl rats with HF have increased half-maximal myofilament calcium sensitivity for tension production. Furthermore, we (25) recently documented decreased half-maximal calcium sensitivity of in vitro velocity of intact thin filaments isolated from Dahl rats with HF (25). This thin filament defect was normalized by chronic bosentan treatment.…”