Development of contractile dysfunction in rat heart failure: hierarchy of cellular events

Abstract

The cellular mechanisms underlying the development of congestive heart failure (HF) are not well understood. Accordingly, we studied myocardial function in isolated right ventricular trabeculae from rats in which HF was induced by left ventricular myocardial infarction (MI). Both early-stage (12 wk post-MI; E-pMI) and late, end-stage HF (28 wk post-Mi; L-pMI) were studied. HF was associated with decreased sarcoplasmic reticulum Ca2+ ATPase protein levels (28% E-pMI; 52% L-pMI). HF affected neither sodium/calcium exchange, ryanodine receptor, nor phospholamban protein levels. Twitch force at saturating extracellular [Ca2+] was depressed in HF (30% E-pMI; 38% L-pMI), concomitant with a marked increase in sensitivity of twitch force toward extracellular [Ca2+] (26% E-pMI; 68% L-pMI). Ca2+-saturated myofilament force development in skinned trabeculae was unchanged in E-pMI but significantly depressed in L-pMI (45%). Tension-dependent ATP hydrolysis rate was depressed in L-pMI (49%), but not in E-pMI. Our results suggest a hierarchy of cellular events during the development of HF, starting with altered calcium homeostasis during the early phase followed by myofilament dysfunction at end-stage HF.

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

“…Because of the high amount of detergent used in the homogenization buffer, it is unlikely that much of the PKC remained in the particulate (myofilament) fraction, and thus the amount of PKC protein in the detergent extracted fraction represents most of the PKC found inside the ventricular myocyte. At an early stage of HF, characterized by preserved myofilament function, 25 we found no changes in PKC-␣ expression or activation ( Figure 1A and 1B). In contrast, PKC-␣ expression was increased Ϸ4-fold in CHF relative to age-matched control ventricles ( Figure 1C).…”

“…Ascending aortic banding and myocardial infarction (MI) were performed on 4-week female Sprague-Dawley rats as described previously, with slight modifications. 11,15 Animals in the early HF cohort were followed for a period of 12 weeks, 25 whereas animals in the end-stage CHF group were followed for 32 to 36 weeks until they transitioned to end-stage CHF. Unoperated age-matched animals served as controls.…”

“…3,29 That is, we and others have shown both in experimental and human CHF a significant blunting of myofilament force development, Ca 2ϩ sensitivity, and cross-bridge cycling kinetics. 3,[11][12][13][14]16,17,25,26,29,30 In transgenic mouse models of HF, reports indicate that increased myocardial concentrations of PKC-␤ and PKC-elicit augmented phosphorylation of cTnI and cTnT coincident with myofilament and ventricular dysfunction. 7,21,22 Moreover, several studies clearly indicate that phosphorylation of cTnI and cTnT by numerous PKC isozymes are central in the control of ventricular myofilament force development, Ca 2ϩ sensitivity, and contractility.…”

Heart failure switches the RV α1-adrenergic inotropic response from negative to positive

“…There is controversy regarding the effects on EC 50 in heart failure, with reports of decreased EC 50 (increased myofilament Ca 2ϩ sensitivity) in heart failure in some, but not all, studies (3,7,12,17,21,30). We found that the effects of heart failure on EC 50 depended on the experimental context.…”

Sex-related changes in cardiac function following myocardial infarction in mice

“…Both of these indexes of cardiac muscle contractility (PRSW and dP/dt max vs. EDV max ), demonstrated a sex-related difference in 10 wk post-MI mice during the decompensation to failure. Despite the activation of neurohormonal compensatory mechanisms, myocyte contractility is depressed in the infarcted heart, partly due to dysregulation of excitation-contraction (E-C) coupling (8,15,19). The expression of key proteins and the signaling components involved in E-C coupling regulation differ between females and males and are associated with slight functional differences (6).…”