Defective sarcolemmal phospholipase C signaling in diabetic cardiomyopathy

Tappia, Paramjit S.; Asemu, Girma; Aroutiounova, Nina; Dhalla, Naranjan S.

doi:10.1023/b:mcbi.0000028756.31782.46

Cited by 27 publications

(17 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, differences in the activity of PLCB isoforms might be important as well. Recently, expression of PLCB3 was reported to be decreased in diabetes (39). We report reduction of PLCB1 expression in kidney of ZDF rats with PLCB1 interacting with TRPC1 (as discussed above), therefore reinforcing the impact of HNF4␣ dysfunction in Ca 2ϩ signaling during diabetic nephropathy.…”

Section: Discussionsupporting

confidence: 73%

HNF4α and the Ca-Channel TRPC1 Are Novel Disease Candidate Genes in Diabetic Nephropathy

Niehof

Borlak

2008

Diabetes

View full text Add to dashboard Cite

OBJECTIVE-The nuclear receptor hepatic nuclear factor 4␣ (HNF4␣) is a master regulatory protein and an essential player in the control of a wide range of metabolic processes. Dysfunction of HNF4␣ is associated with metabolic disorders including diabetes. We were particularly interested in investigating molecular causes associated with diabetic nephropathy.RESEARCH DESIGN AND METHODS-Novel disease candidate genes were identified by the chromatin immunoprecipitation-cloning assay and by sequencing of immunoprecipitated DNA. Expression of candidate genes was analyzed in kidney and liver of Zucker diabetic fatty (ZDF) and of streptozotocin (STZ)-administered rats and after siRNA-mediated silencing of HNF4␣.RESULTS-We identified the calcium-permeable nonselective transient receptor potential cation channel, subfamily C, member 1 (TRPC1) as a novel HNF4␣ gene target. Strikingly, TRPC1 is localized on human chromosome 3q22-24, i.e., a region considered to be a hotspot for diabetic nephropathy. We observed a significant reduction of TRPC1 gene expression in kidney and liver of diabetic ZDF and of STZ-administered rats as a result of HNF4␣ dysfunction. We found HNF4␣ and TRPC1 protein expression to be repressed in kidneys of diabetic patients diagnosed with nodular glomerulosceloris as evidenced by immunohistochemistry. Finally, siRNA-mediated functional knock down of HNF4␣ repressed TRPC1 gene expression in cell culture experiments.CONCLUSIONS-Taken collectively, results obtained from animal studies could be translated to human diabetic nephropathy; there is evidence for a common regulation of HNF4␣ and TRPC1 in human and rat kidney pathologies. We propose dysregulation of HNF4␣ and TRPC1 as a possible molecular rationale in diabetic nephropathy.

show abstract

Section: Discussionsupporting

confidence: 73%

HNF4α and the Ca-Channel TRPC1 Are Novel Disease Candidate Genes in Diabetic Nephropathy

Niehof

Borlak

2008

Diabetes

View full text Add to dashboard Cite

show abstract

“…Both increased and decreased IP 3 production in response to α-adrenergic stimulation has been reported in diabetes [186,187]. PIP 2 levels and the expression and activities of PLC isoenzymes are reduced [188]. Taken together, these data indicate that altered receptor-PLC coupling, IP 3 generation and IP 3 -induced SR Ca 2+ release may contribute to impaired Ca 2+ handling and arrhythmogenesis in diabetic cardiomyopathy.…”

supporting

confidence: 51%

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Kockskämper

Zima

Roderick

et al. 2008

Journal of Molecular and Cellular Cardiology

168

149

View full text Add to dashboard Cite

Inositol 1,4,5-trisphosphate (IP 3 ) is a ubiquitous intracellular messenger regulating diverse functions in almost all mammalian cell types. It is generated by membrane receptors that couple to phospholipase C (PLC), an enzyme which liberates IP 3 from phosphatidylinositol 4,5-bisphosphate (PIP 2 ). The major action of IP 3 , which is hydrophilic and thus translocates from the membrane into the cytoplasm, is to induce Ca 2+ release from endogenous stores through IP 3 receptors (IP 3 Rs). Cardiac excitation-contraction coupling relies largely on ryanodine receptor (RyR)-induced Ca 2+ release from the sarcoplasmic reticulum. Myocytes express a significantly larger number of RyRs compared to IP 3 Rs (∼100:1), and furthermore they experience substantial fluxes of Ca 2+ with each heartbeat. Therefore, the role of IP 3 and IP 3 -mediated Ca 2+ signaling in cardiac myocytes has long been enigmatic. Recent evidence, however, indicates that despite their paucity cardiac IP 3 Rs may play crucial roles in regulating diverse cardiac functions. Strategic localization of IP 3 Rs in cytoplasmic compartments and the nucleus enables them to participate in subsarcolemmal, bulk cytoplasmic and nuclear Ca 2+ signaling in embryonic stem cell-derived and neonatal cardiomyocytes, and in adult cardiac myocytes from the atria and ventricles. Intriguingly, expression of both IP 3 Rs and membrane receptors that couple to PLC/IP 3 signaling is altered in cardiac disease such as atrial fibrillation or heart failure, suggesting the involvement of IP 3 signaling in the pathology of these diseases. Thus, IP 3 exerts important physiological and pathological functions in the heart, ranging from the regulation of pacemaking, excitation-contraction and excitation-transcription coupling to the initiation and/or progression of arrhythmias, hypertrophy and heart failure. KeywordsInositol 1,4,5-trisphosphate; Cardiac myocyte; Calcium; Inotropy; Arrhythmias; Nucleus; Hypertrophy © 2008 Elsevier Inc. All rights reserved. * Corresponding author. E-mail address: jens.kockskaemper@meduni-graz.at (J. Kockskämper).. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript The discovery of IP 3A quarter of a century ago it was shown that D-myo inositol 1,4,5-trisphosphate (IP 3 ) releases Ca 2+ from a non-mitochondrial internal Ca 2+ store [1]. Since this hallmark discovery, IP 3 has emerged as a ubiquitous intracellular messenger, releasing Ca 2+ from stores through activation of IP 3 receptors (IP 3 Rs) in almost all eukaryotic cells. The major IP 3 -sensitive intracellular Ca 2+ store is the endoplasmic reticulum. However, IP 3 has also been shown to release Ca 2+ stored in other compartments, such as the Golgi and the nuclear envelope [2]. In addition, IP 3 Rs are present on the plasma membrane of some cell types, where they can gate Ca 2+ influx [3]. A crucial role for IP 3 -dependent Ca 2+ release has been demonstrated in many mammalian cell types, ranging from tiny platelets, where it initiates blood clottin...

show abstract

“…The diabetic state of the animals was confirmed by the elevated blood glucose and marked reduction in insulin levels following STZ injection (Table 1) as reported in our previous studies (13,(18)(19)(20). Although a further decline in the insulin levels was seen in the 8-wk diabetic animals, this did not result in a further increase in blood glucose levels.…”

Section: General Characteristics and Cardiac Function Of The 4-wk Andsupporting

confidence: 81%

“…The reduced susceptibility of catecholamineinduced arrhythmias could also be, in part, related to the reported decrease in β 1 -and β 2 -adrenoceptors in diabetic hearts (43,44). The α 1 -adrenoceptor is known to modulate intracellular Ca 2+ -concentration through the activation of phospholipase C-mediated generation of inositol trisphosphate and diacylglycerol (20,45). The myocardial α 1 -adrenoceptor signaling system has been reported to be impaired in STZ-induced diabetic rats (46,47).…”

Section: Dose Of Epimentioning

confidence: 99%

Susceptibility of Diabetic Heart to Catecholamine-induced Arrhythmias is Independent of Contractile Dysfunction

Adameová

Elimban²,

Rodriguez-Leyva

et al. 2014

Serbian Journal of Experimental and Clinical Research

Self Cite

View full text Add to dashboard Cite

Background: Diabetes is associated with myocardial electrical instability and prolongation of action potential duration that result in disturbances in the rhythm of the heart. Objective: Th is study was undertaken to examine the role of circulating catecholamines in abnormal cardiac rhythm and contractility during diff erent stages of diabetes. Methods: Diabetes was induced in male Sprague-Dawley rats with streptozotocin (STZ; 65 mg/kg, i.v.). Epinephrine (4-128 μg/kg, i.v.) -induced arrhythmias and plasma levels of epinephrine (Epi) and norepinephrine (NE) were determined in control, 4- and 8-wk diabetic animals. Echocardiography was used to assess cardiac remodeling and contractile function. Results: Although diabetes induced cardiac dysfunction, there were no significant differences in cardiac output, ejection fraction, left ventricle (LV) dimensions, LV fractional shortening between the 4- and 8-wk diabetic animals. Th e electrocardiogram of both diabetic groups showed deep S wave as well as changes in T wave and ST segment. In addition, prolongation of the RR interval in the 4- and 8-wk diabetic animals was seen, while prolongation of the QT and PR intervals were only seen in the 8-wk diabetic animals. Th e severity of Epi-induced ventricular arrhythmias, as assessed by arrhythmia score, was significantly lower in the 8-wk diabetic rats, as compared to the 4-wk diabetic animals. Circulating Epi levels were significantly decreased in the 8-wk diabetic rats, whereas NE levels were increased in the 4-wk diabetic rats. Conclusions: Th e sensitivity of the diabetic heart to catecholamine- triggered arrhythmias may be dependent on circulating Epi rather than NE and thus it can be proposed that the increased incidence of sudden cardiac death in diabetics may not be associated with response to catecholamines.

show abstract

Defective sarcolemmal phospholipase C signaling in diabetic cardiomyopathy

Cited by 27 publications

References 40 publications

HNF4α and the Ca-Channel TRPC1 Are Novel Disease Candidate Genes in Diabetic Nephropathy

HNF4α and the Ca-Channel TRPC1 Are Novel Disease Candidate Genes in Diabetic Nephropathy

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Susceptibility of Diabetic Heart to Catecholamine-induced Arrhythmias is Independent of Contractile Dysfunction

Contact Info

Product

Resources

About