Genetic background influences adaptation to cardiac hypertrophy and Ca2+ handling gene expression

Abstract

Genetic variability has a profound effect on the development of cardiac hypertrophy in response to stress. Consequently, using a variety of inbred mouse strains with known genetic profiles may be powerful models for studying the response to cardiovascular stress. To explore this approach we looked at male C57BL/6J and 129/SvJ mice. Hemodynamic analyses of left ventricular pressures (LVPs) indicated significant differences in 129/SvJ and C57BL/6J mice that implied altered Ca2+ handling. Specifically, 129/SvJ mice demonstrated reduced rates of relaxation and insensitivity to dobutamine (Db). We hypothesized that altered expression of genes controlling the influx and efflux of Ca2+ from the sarcoplasmic reticulum (SR) was responsible and investigated the expression of several genes involved in maintaining the intracellular and sarcoluminal Ca2+ concentration using quantitative real-time PCR analyses (qRT-PCR). We observed significant differences in baseline gene expression as well as different responses in expression to isoproterenol (ISO) challenge. In untreated control animals, 129/SvJ mice expressed 1.68× more ryanodine receptor 2(Ryr2) mRNA than C57BL/6J mice but only 0.37× as much calsequestrin 2 (Casq2). After treatment with ISO, sarco(endo)plasmic reticulum Ca2+-ATPase(Serca2) expression was reduced nearly two-fold in 129/SvJ while expression in C57BL/6J was stable. Interestingly, β (1) adrenergic receptor(Adrb1) expression was lower in 129/SvJ compared to C57BL/6J at baseline and lower in both strains after treatment. Metabolically, the brain isoform of creatine kinase (Ckb) was up-regulated in response to ISO in C57BL/6J but not in 129/SvJ. These data suggest that the two strains of mice regulate Ca2+ homeostasis via different mechanisms and may be useful in developing personalized therapies in human patients.

Manganese‐enhanced MRI detection of impaired calcium regulation in a mouse model of cardiac hypertrophy

“…Furthermore, the high concentration (125 mM) and dose (500 nmol/kg) of Mn ensure that Mn availability is not limiting. In addition, these results are consistent with other investigations demonstrating decreased calcium uptake in the heart following ISO treatment (57,60). Thus, the conclusion that the measured decrease in Mn uptake is a result of ISO-induced hypertrophy and not of relative changes in perfusion or Mn uptake to other organ systems remains the most parsimonious interpretation of these data.…”

“… showed that 129SV/J mice differ from C57 mice in SR calcium content, left‐ventricular ejection fraction, fractional shortening and cellular volume. Previous work from our laboratory demonstrated increased sensitivity to ISO‐induced cardiac hypertrophy in 129SV/J mice, as measured by HW/BW . Although no differences between the strains were observed under baseline conditions, it is possible that increased cardiac stress caused by exercise or positive inotropic stimulation (e.g.…”

Assessing Cardiac Metabolism

“…Although rodent strain selection has always been part of any study design, the increased availability and use of genetically modified rodents, particularly mice, as model systems for human diseases has revolutionized the way we conduct research in general while increasing awareness about the influence of genetic background on the resulting phenotype, which encompasses the cardiac phenotype. For example, many studies have reported mouse strain variations for cardiac function, 38,39 response to β-adrenergic stimulation 40 and angiotensin II, 41 and capacity for calcium handling, 42,43 but also for susceptibility to specific pathophysiological states, such as myocardial hypertrophy 44,45 or heart failure. 46 In terms of cardiac metabolism, only a few studies have made a systematic comparison among commonly used control mouse strains.…”

The active zone protein CAST regulates synaptic vesicle recycling and quantal size in the mouse hippocampus

“…Thus, this difference in the genetic background most likely explains the discrepancies between their and our studies (Crawley et al ., ; Kiselycznyk & Holmes, ). Furthermore, increasing evidence suggests that there are prominent differences in the performance in behavioural tasks, the pattern of protein expression and synaptic physiology among various mouse strains (Waters et al ., ; Lenselink et al ., ; Rubenstein et al ., ; Zhang et al ., ).…”