Calcium homeostasis behavior and cardiac function on left ventricular remodeling by pressure overload (original) (raw)
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Abnormalities of Calcium Cycling in the Hypertrophied and Failing Heart
Journal of Molecular and Cellular Cardiology, 2000
deterioration of cardiac contractility is a central feature of congestive heart failure (CHF) in humans. In this report we review those studies that have addressed the idea that alterations of intracellular calcium (Ca 2+ ) regulation is primarily responsible for the depressed contractility of the failing heart. The review points out that Ca 2+ transients and contraction are similar in non-failing and failing myocytes at very slow frequencies of stimulation (and other low stress environments). Faster pacing rates, high Ca 2+ and -adrenergic stimulation reveal large reductions in contractile reserve in failing myocytes. The underlying cellular basis of these defects is then considered. Studies showing changes in the abundance of L-type Ca 2+ channels, Ca 2+ transport proteins [sarcoplasmic reticulum Ca 2+ ATPase (SERCA2), phospholamban (PLB), Na + /Ca 2+ exchanger (NCX)] and Ca 2+ release channels (RYR) in excitation-contraction coupling and Ca 2+ release and uptake by the sarcoplasmic reticulum (SR) are reviewed. These observations support our hypotheses that (i) defective Ca 2+ regulation involves multiple molecules and processes, not one molecule, (ii) the initiation and progression of CHF inolves defective Ca 2+ regulation, and (iii) prevention or correction of Ca 2+ regulatory defects in the early stages of cardiac diseases can delay or prevent the onset of CHF.
Journal of Cardiac Failure, 2009
Background: Expression and phosphorylation of the cardiac Na þ -Ca 2þ exchanger-1 (NCX-1) are upregulated in heart failure (HF). We examined the effects of chronic cardiac contractility modulation (CCM) therapy on the expression and phosphorylation of NCX-1 and its regulators GATA-4 and FOG-2 in HF dogs. Methods and Results: Studies were performed in LV tissue from 7 CCM-treated HF dogs, 7 untreated HF dogs, and 6 normal (NL) dogs. mRNA expression of NCX-1, GATA-4, and FOG-2 was measured using reverse transcriptase polymerase chain reaction, and protein level was determined by Western blotting. Phosphorylated NCX-1 (P-NCX) was determined using a phosphoprotein enrichment kit. Compared with NL dogs, NCX-1 mRNA and protein expression and GATA-4 mRNA and protein expression increased in untreated HF dogs, whereas FOG-2 expression decreased. Compared with NL dogs, the level of P-NCX-1 normalized to total NCX-1 increased in untreated HF dogs (0.80 6 0.10 vs 0.37 6 0.04; P ! .05). CCM therapy normalized NCX-1 expression, GATA-4, and FOG-2 expression, and the ratio of P-NCX-1 to total NCX-1 (0.62 6 0.10). Conclusion: Chronic monotherapy with CCM restores expression and phosphorylation of NCX-1. These findings are consistent with previous observations of improved LV function and normalized sarcoplasmic reticulum calcium cycling in the left ventricles of HF dogs treated with CCM therapy. (J Cardiac Fail 2009;15:48e56)
Myocardial force and intracellular Ca2+ in an animal model of hypertensive heart failure
Hypertensive heart failure has long been associated with diminished cardiac contractile function, yet the underlying cellular mechanisms are not well understood. The aim of this Thesis was to investigate the relationship between intracellular calcium ([Ca2+]i) and isometric force during the relatively narrow time frame in which long-standing compensated hypertrophy progresses to decompensated end-stage heart failure in an animal model of human essential hypertension. In order to carry out this aim, left ventricular trabeculae were utilized from failing hearts of spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto (WKY) controls. At a physiological stimulation frequency (5 Hz), and temperature (37 °C), the peak stress of SHR trabeculae was significantly reduced compared to WKY, although no differences in the time-course of the twitch were detected. Measurements using fura-2/AM as an index of intracellular [Ca2+] showed that, for SHR, both the peak of the Ca2+ tr...
Cardiovascular Research, 2004
Decreased amplitude and slower kinetics of cardiomyocyte intracellular calcium (Ca 2 + i ) transients may underlie the diminished cardiac function observed in heart failure. These alterations occur in humans and animals with heart failure, including the TNF1.6 mouse model, in which heart failure arises from cardiac-specific overexpression of tumor necrosis factor a (TNFa). Objective: Since ablation of phospholamban expression (PLBKO) removes inhibition of the sarcoplasmic reticulum (SR) Ca 2 + pump, enhances SR Ca 2 + uptake and increases contractility, we assessed whether ablation of phospholamban expression could improve cardiac function, limit remodeling, and improve survival in the TNF1.6 model of heart failure. Methods: We bred PLBKO with TNF1.6 mice and characterized the progeny for survival, cardiac function (echocardiography), cardiac remodeling (hypertrophy, dilation, fibrosis), and Ca 2 + i transients and contractile function of isolated cardiomyocytes. Results: PLB ablation did not improve survival, cardiac function, or limit cardiac chamber dilation and hypertrophy in TNF1.6 mice (TKO mice). However, contractile function and Ca 2 + i transients (amplitude and kinetics) of isolated TKO cardiomyocytes were markedly enhanced. This discordance between unimproved cardiac function, and enhanced Ca 2 + i cycling and cardiomyocyte contractile parameters may arise from a continued overexpression of collagen and decreased expression of gap junction proteins (connexin 43) in response to chronic TNFa stimulation. Conclusions: Enhancement of intrinsic cardiomyocyte Ca 2 + i cycling and contractile function may not be sufficient to overcome several parallel pathophysiologic processes present in the failing heart.
European Heart Journal, 2009
The Tako-Tsubo cardiomyopathy (TTC) is characterized by a transient contractile dysfunction that has been assigned to excessive catecholamine levels after episodes of severe emotional or physical stress. Several studies have indicated that b-adrenoceptor stimulation is associated with alteration in gene expression of Ca 2þ -regulatory proteins. Thus, the present study investigated the gene expression of crucial proteins [sarcoplasmic Ca 2þ ATPase (SERCA2a), sarcolipin (SLN), phospholamban (PLN), ryanodine receptor (RyR2), and sodium-calcium exchanger (NCX)] involved in the Ca 2þ -regulating system in TTC.
Cell Calcium, 2017
Recent studies have implicated a relationship between RhoA/ROCK activity and defective Ca 2+ homeostasis in hypertrophic hearts. This study investigated molecular mechanism underlying ROCK inhibition-mediated cardioprotection against pressure overload-induced cardiac hypertrophy, with a focus on Ca 2+ homeostasis. Cardiac hypertrophy model was established by performing transverse aortic constriction (TAC) in 8-week-old male rats. Groups were assigned as SHAM, TAC and TAC + Fas (rats undergoing TAC and treated with fasudil). Rats in the TAC + Fas group were administered fasudil (5 mg/kg/day), and rats in the SHAM and TAC groups were treated with vehicle for 10 weeks. Electrophysiological recordings were obtained from isolated left ventricular myocytes and expression levels of proteins were determined using western blotting. Rats in the TAC group showed remarkable cardiac hypertrophy, and fasudil treatment significantly reversed this alteration. TAC + Fas myocytes showed significant improvement in reduced contractility and Ca 2+ transients. Moreover, these myocytes showed restoration of slow relaxation rate and Ca 2+ reuptake. Although L-type Ca 2+ currents did not change in TAC group, there was a significant reduction in the triggered Ca 2+ transients which was reversed either by long-term fasudil treatment or incubation of TAC myocytes with fasudil. The hearts of rats in the TAC group showed a significant decrease in ROCK1, ROCK2, RyR2 protein levels and p-PLB S16/T17 /SERCA2 ratio and increase in RhoA expression and MLC phosphorylation. However, fasudil treatment largely reversed TAC-induced alterations in protein expression. Thus, our findings indicate that upregulation of the RhoA/ROCK pathway is significantly associated with cardiac hypertrophy-related Ca 2+ dysregulation and suggest that ROCK inhibition prevents hypertrophic heart failure.