Role of SR Ca²⁺-ATPase in contractile dysfunction of myocytes in tachycardia-induced heart failure

Abstract

Sarcoplasmic reticulum (SR) Ca2+-ATPase gene expression is reduced in the failing myocardium. However, the functional relevance of these changes to myocardial contractility is not yet established. We assessed myocardial contractile function by analyzing sarcomere motion of isolated myocytes and also quantified SR Ca2+ regulatory protein gene expression by Northern blot analysis in the same hearts obtained from 10 dogs with pacing-induced heart failure (HF; 240 beats/min, 4 wk) and 7 control dogs. Sarcomere-shortening velocity was depressed in HF myocytes, accompanied by the prolongation of intracellular Ca2+ concentration ([Ca2+]i) transient measured by indo 1 fluorescence ratio. SR Ca2+-ATPase mRNA levels (normalized to glyceraldehyde-3-phosphate dehydrogenase mRNA) were significantly depressed in HF, and calsequestrin mRNA was increased. For control and HF dogs, sarcomere-shortening velocity correlated positively with Ca2+-ATPase mRNA levels ( r = 0.73, n = 17, P < 0.01) but not with calsequestrin mRNA. Ca2+-ATPase mRNA levels were correlated with45Ca2+uptake rate by SR, which was also reduced in HF. Moreover, the inhibition of SR Ca2+-ATPase with thapsigargin or cyclopiazonic acid reproduced in normal myocytes the abnormalities observed in HF myocytes, such as depressed contractility and the prolonged [Ca2+]itransient duration. A downregulation of Ca2+-ATPase gene expression and a resultant decrease in Ca2+ uptake by SR may be responsible for the contractile dysfunction and the alterations of [Ca2+]itransient in HF.

Defective glycosylation of calsequestrin in heart failure

“…differences in glycoform components were in contrast to a lack of statistically significant difference ( p =0.56) seen in total protein (Fig. 3B, leftmost histogram), consistent with previous findings in rapid-paced dogs [25,34].…”

Defective Regulation of Interdomain Interactions Within the Ryanodine Receptor Plays a Key Role in the Pathogenesis of Heart Failure

“…21 In brief, a wedge of LV free wall perfused by a branch of the left circumflex coronary artery was dissected free of the heart and perfused with collagenase-containing buffer. LV myocardium was minced with scissors in fresh collagenasecontaining buffer.…”

Role of Subcellular Remodeling in Cardiac Dysfunction due to Congestive Heart Failure

“…In a report by Movsesian and Schwinger [58] , there are findings that show a reduction in the Ca 2+ sequestration of the failing human myocardium; this is consistent with those of the animal models and can be attributed to decreased levels of SERCA mRNA. Further studies supporting this decrease in SERCA expression and function in the failing heart were carried out in experimental models of the pressure-overloaded rat [49] , the tachycardia-induced mongrel dog [59] , the volume-overloaded rat [60] , infarcted rats [61] and the transgenically engineered hypertensive rat [62] . Though this offers insight into the molecular basis for the pathogenesis of CHF, the data that is accumulated raises more questions than that which have been answered.…”