Enhanced Ca2+ influx through cardiac L-type Ca2+ channels maintains the systolic Ca2+ transient in early cardiac atrophy induced by mechanical unloading

Abstract

Cardiac atrophy as a consequence of mechanical unloading develops following exposure to microgravity or prolonged bed rest. It also plays a central role in the reverse remodelling induced by left ventricular unloading in patients with heart failure. Surprisingly, the intracellular Ca2+ transients which are pivotal to electromechanical coupling and to cardiac plasticity were repeatedly found to remain unaffected in early cardiac atrophy. To elucidate the mechanisms underlying the preservation of the Ca2+ transients, we investigated Ca2+ cycling in cardiomyocytes from mechanically unloaded (heterotopic abdominal heart transplantation) and control (orthotopic) hearts in syngeneic Lewis rats. Following 2 weeks of unloading, sarcoplasmic reticulum (SR) Ca2+ content was reduced by ~55 %. Atrophic cardiac myocytes also showed a much lower frequency of spontaneous diastolic Ca2+ sparks and a diminished systolic Ca2+ release, even though the expression of ryanodine receptors was increased by ~30 %. In contrast, current clamp recordings revealed prolonged action potentials in endocardial as well as epicardial myocytes which were associated with a two to fourfold higher sarcolemmal Ca2+ influx under action potential clamp. In addition, Cav1.2 subunits which form the pore of L-type Ca2+ channels (LTCC) were upregulated in atrophic myocardium. These data suggest that in early cardiac atrophy induced by mechanical unloading, an augmented sarcolemmal Ca2+ influx through LTCC fully compensates for a reduced systolic SR Ca2+ release to preserve the Ca2+ transient. This interplay involves an electrophysiological remodelling as well as changes in the expression of cardiac ion channels.

Physiologic force-frequency response in engineered heart muscle by electromechanical stimulation

“…Transients were recorded at room temperature under 1 Hz stimulation and analyzed using IonWizard software (IonOptix). Cardiomyocytes were additionally treated with a rapid administration of caffeine (10 mmol/L, Calbiochem) or thapsigargin (45) (1 μmol/L, Calbiochem) for 3 minutes, to assess SR storage capacity and dependence on SERCA-mediated Ca 2+ re-uptake from the cytosol, respectively.…”

Sarcolemmal Alterations in Unloaded Rat Heart after Heterotopic Transplantation

“…Such an alteration in the sarcolemmal function may be adaptive in nature because Ca 2þ pump mechanism in the sarcoplasmic reticulum, which is considered to play a major role in lowering the cytoplasmic Ca 2þ concentration, 6,8 has been shown to be impaired in the transplanted atrophied hearts. 4,5 Augmentation of the mechanisms in sarcolemma for lowering the cytoplasmic concentration of Ca 2þ and depression of those at the sarcoplasmic reticulum have also been reported for the aging myocardium 25 and stable cardiac hypertrophy. 10,26 Such differential changes in Ca 2þ transport activities at the sarcolemma and sarcoplasmic reticulum may explain the ability of cardiac muscle from the transplanted hearts to exhibit normal contractile activity at stimulation frequencies less than 24 stimuli/minute or at calcium concentrations less than 2 mM calcium.…”

“…It should be mentioned that electrophysiological studies have also shown unaltered density of the Na þ -Ca 2þ exchange current in atrophied heart. 5 However, several studies have reported changes in the Na þ -dependent Ca 2þ uptake and Na þinduced Ca 2þ release activities independent of each other under a variety of different experimental conditions. 10,[16][17][18][19][20][21] On the other hand, the observed increase in ATP-dependent Ca 2þ uptake activity may be due to higher Ca 2þ -stimulated ATPase activity in the transplanted heart, since this enzyme is considered to serve as Ca 2þ pump in the sarcolemmal membrane.…”

“…10,[16][17][18][19][20][21] On the other hand, the observed increase in ATP-dependent Ca 2þ uptake activity may be due to higher Ca 2þ -stimulated ATPase activity in the transplanted heart, since this enzyme is considered to serve as Ca 2þ pump in the sarcolemmal membrane. 8 Such changes in the sarcolemmal Ca 2þ transport system may be considered as an adaptive mechanism for maintaining the intracellular concentration of Ca 2þ within normal range because Ca 2þ influx through L-type Ca 2þ channels is increased 5 and Ca 2þ uptake by sarcoplasmic reticulum is reduced 4,5 in the transplanted atrophied heart. Increased sarcolemmal Ca 2þ pump activity has also been observed in the hypothyroid atrophied rat heart.…”

A New Animal Model for Investigation of Mechanical Unloading in Hypertrophic and Failing Hearts: Combination of Transverse Aortic Constriction and Heterotopic Heart Transplantation

“…Nonetheless, CF and mechanical unloading are non-physiological conditions for the myocardium and vessels. In experimental models of unloading severe alterations occur in micro ribonucleic acid expression, in cardiac electrophysiology, in the phosphorylation of cardiac regulatory proteins and cardiac atrophy [7][8][9][10]. Clinically it frequently leads to gastrointestinal bleeding due to arteriovenous malformation [11].…”