Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sorcin is a penta-EF hand Ca2+-binding protein that associates with both cardiac ryanodine receptors and L-type Ca2+ channels and has been implicated in the regulation of intracellular Ca2+ cycling. To better define the function of sorcin, we characterized transgenic mice in which sorcin was overexpressed in the heart. Transgenic mice developed normally with no evidence of cardiac hypertrophy and no change in expression of other calcium regulatory proteins. In vivo hemodynamics revealed significant reductions in global indices of contraction and relaxation. Contractile abnormalities were also observed in isolated adult transgenic myocytes, along with significant depression of Ca2+ transient amplitudes. Whole cell ICa density and the time course of activation were normal in transgenic myocytes, but the rate of inactivation was significantly accelerated. These effects of sorcin on L-type Ca2+ currents were confirmed in Xenopus oocyte expression studies. Finally, we examined the expression of sorcin in normal and failing hearts from spontaneous hypertensive heart failure rats. In normal myocardium, sorcin extensively co-localized with ryanodine receptors at the Z-lines, whereas in myopathic hearts the degree of co-localization was markedly disrupted. Together, these data indicate that sorcin modulates intracellular Ca2+ cycling and Ca2+ influx pathways in the heart.
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PMID:Sorcin regulates excitation-contraction coupling in the heart. 1275 54

In many types of heart failure cardiac myocyte Ca(2+) handling is abnormal because of downregulation of key Ca(2+) - handling proteins like sarco(endo)plasmic reticulum Ca(2+) - ATPase (SERCA)2a and ryanodine receptor (RyR)2. The alteration in SERCA2a and RyR2 expression results in altered cytosolic Ca(2+) transients, leading to abnormal contraction. Sorcin is an EF-hand protein that confers the property of caffeine-activated intracellular Ca(2+) release in nonmuscle cells by interacting with RyR2. To determine whether sorcin could improve the contractile function of the heart, we overexpressed sorcin in the heart of either normal or diabetic mice and in adult rat cardiomyocytes with an adenoviral gene transfer approach. Sorcin overexpression was associated with an increase in cardiac contractility of the normal heart and dramatically rescued the abnormal contractile function of the diabetic heart. These effects could be attributed to an improvement of the Ca(2+) transients found in the cardiomyocyte after sorcin overexpression. Viral vector-mediated delivery of sorcin to cardiac myocytes is beneficial, resulting in improved contractile function in diabetic cardiomyopathy.
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PMID:In vivo adenoviral transfer of sorcin reverses cardiac contractile abnormalities of diabetic cardiomyopathy. 1295 30

Sorcin (SOR), an EF-hand Ca(2+)-binding protein, interacts with the sarcolemmal proteins Annexin VII and L-type Ca(2+)-channel and with the sarcoplasmic reticulum (SR) Ca(2+)-release channel (ryanodine-receptor, RYR), and has been implicated to influence the intracellular Ca(2+)-homeostasis. The present study aimed at investigating the effects of increased SOR expression on force development and relaxation in virus transfected rat hearts and isolated cardiomyocytes. We generated an adenovirus encoding the SOR coding DNA with a separate cassette for green fluorescent protein (GFP) both driven by the CMV-promoter to induce SOR-overexpression (Ad.SOR.GFP). As control served an adenovirus carrying an empty cassette with a separate cassette for GFP also driven by CMV-promoters (Ad.GFP). Cardiomyocytes of healthy male rats were isolated, transfected and cultured for 48 h with Ad.SOR.GFP as well as Ad.GFP as control. In addition, Ad.SOR.GFP was injected into coronary arteries via a catheter-based technique and rat hearts were transfected in vivo for 12 days. Echocardiography was performed to assess cardiac function at 7 and 12 days before the animals were sacrificed. A 1.7-fold increase of the SOR protein amount in cultured myocytes treated with Ad.SOR.GFP compared to Ad.GFP-transfected cells indicated a successful overexpression of SOR. Cell-contracting experiments using infected cardiomyocytes (transfection: 48 h; frequency: 0.5 Hz) exhibited a significantly higher peak force of contraction (FOC) in the SOR-overexpression group (n = 64) vs. control (n = 21) (6.8% +/- 0.2% vs. 4.3% +/- 0.1%). Beta-adrenergic stimulation with forskolin resulted in similar increases in FOC. Echocardiography of in vivo transfected rat hearts exhibited enhanced fractional shortening (65.9 +/- 5.5% vs. 79.3 +/- 2.5%) and decreased end-systolic diameters indicating enhanced cardiac contractility. Gross morphology was similar in both groups after 14 days of transfection. These results strengthen the notion that overexpression of SOR improves cardiac contractility independent of beta-adrenergic stimulation and may prove beneficial in the treatment of decreased cardiac output such as heart failure.
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PMID:Overexpression of sorcin enhances cardiac contractility in vivo and in vitro. 1580 37

Calcium (Ca2+) plays an important role as a messenger in the excitation-contraction coupling process of the myocardium. It is stored in the sarcoplasmic reticulum (SR) and released via a calcium release channel called the ryanodine receptor. Cardiac ryanodine receptor (RyR2) controls Ca2+ release, which is essential for cardiac contractility. There are several molecules which bind and regulate the function of RyR2 including calstabin2, calmodulin, protein kinase A (PKA), phosphatase, sorcin and calsequestrin. Alteration of RyR2 and associated molecules can cause functional and/or structural changes of the heart, leading to heart failure and sudden cardiac death. In this review, the alteration of RyR2 and its regulatory proteins, and its roles in heart failure and sudden cardiac death, are discussed. Evidence of a possible novel therapy targeting RyR2 and its associated regulatory proteins, currently proposed by investigators, is also included in this article.
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PMID:Roles of cardiac ryanodine receptor in heart failure and sudden cardiac death. 1670 9

Abnormal release of Ca(2+) from sarcoplasmic reticulum (SR) via the cardiac ryanodine receptor (RyR2) may contribute to contractile dysfunction in heart failure (HF). We previously demonstrated that RyR2 macromolecular complexes from HF rat were significantly more depleted of FK506 binding protein (FKBP12.6). Here we assessed expression of key Ca(2+) handling proteins and measured SR Ca(2+) content in control and HF rat myocytes. Direct measurements of SR Ca(2+) content in permeabilized cardiac myocytes demonstrated that SR luminal [Ca(2+)] is markedly lowered in HF (HF: DeltaF/F(0) = 26.4+/-1.8, n=12; control: DeltaF/F(0) = 49.2+/-2.9, n=10; P<0.01). Furthermore, we demonstrated that the expression of RyR2 associated proteins (including calmodulin, sorcin, calsequestrin, protein phosphatase 1, protein phosphatase 2A), Ca(2+) ATPase (SERCA2a), PLB phosphorylation at Ser16 (PLB-S16), PLB phosphorylation at Thr17 (PLB-T17), L-type Ca(2+) channel (Cav1.2) and Na(+)- Ca(2+) exchanger (NCX) were significantly reduced in rat HF. Our results suggest that systolic SR reduced Ca(2+) release and diastolic SR Ca(2+) leak (due to defective protein-protein interaction between RyR2 and its associated proteins) along with reduced SR Ca(2+) uptake (due to down-regulation of SERCA2a, PLB-S16 and PLB-T17), abnormal Ca(2+) extrusion (due to down-regulation of NCX) and defective Ca(2+) -induced Ca(2+) release (due to down-regulation of Cav1.2) could contribute to HF.
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PMID:Defective Ca(2+) handling proteins regulation during heart failure. 2094 56

MicroRNAs are negative gene regulators and play important roles in cardiac development and disease. As evident by cardiomyopathy following cardiac-specific Dicer knockdown they also are required for maintaining normal cardiac contractile function but the specific role of miR-1 in the process is poorly understood. To characterize the role of miR-1 in particular and to identify its specific targets we created a tamoxifen-inducible, cardiac-specific Dicer knockdown mouse and demonstrated that Dicer downregulation results in a dramatic and rapid decline in cardiac function concurrent with significantly reduced levels of miR-1. The importance of miR-1 was established by miR-1 antagomir treatment of wild-type mice, which replicated the cardiac-specific Dicer knockdown phenotype. Down-regulation of miR-1 was associated with up-regulation of its predicted target Sorcin, an established modulator of calcium signaling and excitation-contraction coupling, subsequently verified as a miR-1 target with luciferase constructs. siRNA-mediated knockdown of Sorcin effectively rescued the cardiac phenotypes after Dicer or miR-1 knockdown affirming Sorcin as a critical mediator of the acute cardiomyopathy observed. The regulatory relationship between miR-1 and Sorcin was further confirmed in cultured mouse cardiomyocytes where modulation of miR-1 was associated with discordant Sorcin levels and dysregulation of calcium signaling. Pathological relevance of our findings included decreased miR-1 and increased Sorcin expression in end-stage cardiomyopathy. These findings demonstrate the importance of miR-1 in cardiac function and in the pathogenesis of heart failure via Sorcin-dependent calcium homeostasis.
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PMID:miR-1 mediated suppression of Sorcin regulates myocardial contractility through modulation of Ca2+ signaling. 2232 46