Regulation of myocardial function by histidine-rich, calcium-binding protein

Abstract

Impaired sarcoplasmic reticulum (SR) Ca release has been suggested to contribute to the depressed cardiac function in heart failure. The release of Ca from the SR may be regulated by the ryanodine receptor, triadin, junctin, calsequestrin, and a histidine-rich, Ca-binding protein (HRC). We observed that the levels of HRC were reduced in animal models and human heart failure. To gain insight into the physiological function of HRC, we infected adult rat cardiac myocytes with a recombinant adenovirus that contains the full-length mouse HRC cDNA. Overexpression (1.7-fold) of HRC in adult rat cardiomyocytes was associated with increased SR Ca load (28%) but decreased SR Ca-induced Ca release (37%), resulting in impaired Ca cycling and depressed fractional shortening (36%) as well as depressed rates of shortening (38%) and relengthening (33%). Furthermore, the depressed basal contractile and Ca kinetic parameters in the HRC-infected myocytes remained significantly depressed even after maximal isoproterenol stimulation. Interestingly, HRC overexpresssion was accompanied by increased protein levels of junctin (1.4-fold) and triadin (1.8-fold), whereas the protein levels of ryanodine receptor, calsequestrin, phospholamban, and sarco(endo)plasmic reticulum Ca-ATPase remained unaltered. Collectively, these data indicate that alterations in expression levels of HRC are associated with impaired cardiac SR Ca homeostasis and contractile function.

Designing Heart Performance by Gene Transfer

“…The Ca 2ϩ binding ability of HRC and its interaction with junctional proteins suggest a potentially important physiological role of HRC in cardiac function. Adenoviral-mediated acute gene transfer of HRC demonstrated a direct and significant inhibitory effect on the Ca 2ϩ transient and myocyte contractility when overexpressed at low levels of ϳ1.7-fold (223). In this study, HRC overexpression slowed Ca 2ϩ transient decay and as a consequence myocyte relaxation (223 (223).…”

Increased Ca2+ storage capacity of the skeletal muscle sarcoplasmic reticulum of transgenic mice over‐expressing membrane bound calcium binding protein junctate

“…Indeed chronic over-expression of calsequestrin, the major Ca 2þ binding protein in striated muscle in cardiomyocytes, increased the Ca 2þ storage capacity of the SR but did not affect the expression level of SERCA or phospholamban (Jones et al, 1998;Sato et al, 1998;Knollmann et al, 2000;Miller et al, 2005). Consistent results showing an increase in the lumenal SR Ca 2þ buffering capacity were obtained when the luminal histidine-rich Ca 2þ binding protein (HRC) was over-expressed in neonatal and adult rat cardiomyocytes (Kim et al, 2003;Fan et al, 2004). Similar results were also described when Fig.…”

“…Furthermore, over-expression of other known calcium storage proteins such as calsequestrin and histidine rich Ca 2þ binding protein leads to an increase in caffeine-induced Ca 2þ release (Jones et al, 1998;Sato et al, 1998;Kim et al, 2003;Fan et al, 2004;Miller et al, 2005). Over-expression of junctate also occurs in a membrane compartment endowed with the RyR Ca 2þ release channel, since we found that (i) direct stimulation of isolated myotubes with either caffeine or 4-CmC resulted in a significantly larger Ca 2þ transient and (ii) total SR microsomes from transgenic mice show a 24% increase of the extent of calcium release induced by 4-CmC.…”

Junctin is a prominent regulator of contractility in cardiomyocytes

“…Adult rat ventricular myocytes were obtained from Langendorff-perfused hearts of male Sprague-Dawley rats (∼300mg, Harlan Laboratory) at 37°C, as described before [13]. Briefly, rats were anesthetized with sodium pentobarbital (50mg/kg IP) and heparinized (10,000U/kg IP).…”