Advanced glycation end products (AGEs) are produced through the non enzymatic glycation and oxidation of proteins, lipids and nucleic acids. Enhanced formation of AGEs occurs particularly in conditions associated with hyperglycaemia such as diabetes mellitus (DM). AGEs are believed to have a key role in the development and progression of cardiovascular disease in patients with DM through the modification of the structure, function and mechanical properties of tissues through crosslinking intracellular as well as extracellular matrix proteins and through modulating cellular processes through binding to cell surface receptors [receptor for AGEs (RAGE)]. A number of studies have shown a correlation between serum AGE levels and the development and severity of heart failure (HF). Moreover, some studies have suggested that therapies targeted against AGEs may have therapeutic potential in patients with HF. The purpose of this review is to discuss the role of AGEs in cardiovascular disease and in particular in heart failure, focussing on both cellular mechanisms of action as well as highlighting how targeting AGEs may represent a novel therapeutic strategy in the treatment of HF.

Background:Previously we have shown that PMCA4 interacts with nNOS. Results: In PMCA4Ϫ/Ϫ mice, plasma membrane-associated nNOS protein was delocalized to the cytosol with no change in total

The cardiac neuronal nitric-oxide synthase (nNOS) has been described as a modulator of cardiac contractility. We have demonstrated previously that isoform 4b of the sarcolemmal calcium pump (PMCA4b) binds to nNOS in the heart and that this complex regulates ␤-adrenergic signal transmission in vivo. Here, we investigated whether the nNOS-PMCA4b complex serves as a specific signaling modulator in the heart. PMCA4b transgenic mice (PMCA4b-TG) showed a significant reduction in nNOS and total NOS activities as well as in cGMP levels in the heart compared with their wild type (WT) littermates. In contrast, PMCA4b-TG hearts showed an elevation in cAMP levels compared with the WT. Adult cardiomyocytes isolated from PMCA4b-TG mice demonstrated a 3-fold increase in Ser 16 phospholamban (PLB) phosphorylation as well as Ser 22 and Ser 23 cardiac troponin I (cTnI) phosphorylation at base line compared with the WT. In addition, the relative induction of PLB phosphorylation and cTnI phosphorylation following isoproterenol treatment was severely reduced in PMCA4b-TG myocytes, explaining the blunted physiological response to the ␤-adrenergic stimulation. In keeping with the data from the transgenic animals, neonatal rat cardiomyocytes overexpressing PMCA4b showed a significant reduction in nitric oxide and cGMP levels. This was accompanied by an increase in cAMP levels, which led to an increase in both PLB and cTnI phosphorylation at base line. Elevated cAMP levels were likely due to the modulation of cardiac phosphodiesterase, which determined the balance between cGMP and cAMP following PMCA4b overexpression. In conclusion, these results showed that the nNOSPMCA4b complex regulates contractility via cAMP and phosphorylation of both PLB and cTnI.

Advanced glycation end products (AGE) are central to the development of cardiovascular complications associated with diabetes mellitus. AGE may alter cellular function through cross‐linking of cellular proteins or by activating the AGE receptor (RAGE). However, the signalling molecules involved during AGE stimulation in cardiomyocytes remain unclear. Here, we investigated the effects of AGE treatment on intracellular calcium homeostasis of isolated cardiomyocytes and studied the activation of signalling molecules involved in this process. Treatment of cardiomyocytes with AGE for 24 h resulted in a dose‐dependent reduction in calcium transient amplitude, reaching a maximum 50% reduction at a dose of 1 mg·mL−1. This was accompanied with a 32% reduction in sarcoplasmic reticulum calcium content but without any detectable changes in the expression of major calcium channels. Mechanistically, we observed a significant increase in the production of reactive oxygen species (ROS) in AGE‐treated cardiomyocytes and enhancement of NADPH oxidase activity. This was accompanied with activation of p38 kinase and nuclear translocation of NF‐κB, and subsequently induction of inducible NO synthase (iNOS) expression, leading to excessive nitric oxide production. Overall, our data reveal the molecular signalling that may underlie the alteration of intracellular calcium homeostasis in cardiac myocytes due to AGE stimulation. This may provide new insights into the pathophysiological mechanisms of the development of diabetic cardiomyopathy.

No abstract

coronary flow and is an important predictor of coronary microvascular function. A variety of environmental stimuli have been shown to affect CFR but little is known about the genetic component of CFR. To characterise the genetics of CFR we initially measured in vivo blood pressure (BP) and ex vivo cardiac phenotypes including CFR in two inbred rat strains, Brown Norway (BN) and Spontaneously Hypertensive Rat (SHR) which is a genetic model for hypertension and microvascular dysfunction. We then studied BP and coronary flow (CF) phenotypes in F 1 and F 2 crosses derived from BN and SHR to estimate the heritability of CFR and its relationship with BP. Methods Animals were anaesthetized using a mixture of Oxygen and Isoflurane. BP was measured invasively by cannulation of carotid artery. Following BP measurement hearts were excised and rapidly transferred to the ex vivo perfusion apparatus where retrograde perfusion was established using the Langendorff technique. Hearts were perfused with Carbogen buffered Kreb 9 s solution and paced constantly at 360 bpm. A fluid filled balloon was placed in the left ventricular (LV) cavity to measure the pressure indices. CF, LV developed pressure, myocardial contractility (LV dP/dt max) and myocardial relaxation (LV dP/dt min) were recorded at baseline, during peak hyperaemia, regional ischaemia (induced by ligation of the proximal left anterior descending artery) and reperfusion. Results 1) CFR differs significantly between the two inbred parental rat strains. (BN¼2.1 6 0.32, SHR¼1.5 6 0.18, p¼2.6310 À7 , n¼16 each). 2) Heritability of CFR: Broad sense heritability (the proportion of total phenotypic variance attributable to total genetic variance) for CFR is 62% indicating a large and previously unrecognised genetic component of CFR. 3) Relationship between CFR and BP: We did not find statistically significant correlation between CFR and BP in the F 2 intercross (r¼0.11, p¼0.11, n¼176). 4) Relationship between CF and myocardial relaxation (LV dP/dt min): LV dP/dt min correlated strongly with CF during all stages of the experiment (baseline CF, r¼À0.36, p<0.0001, reperfusion CF, r¼À0.40, p<0.0001). Conclusions Our results demonstrate that CFR has a significant genetic component and is largely independent of BP effects. Furthermore we demonstrate a very significant relationship between CF and LV dP/dt min indicating a link between LV diastolic dysfunction and impaired CF. Using 768 SNP genotyping assay for linkage mapping and gene expression analysis with Affymetrix rat gene chip, we will determine the quantitative trait loci and transcripts associated with CFR to improve our understanding of the genomic architecture of CFR.

No abstract

No abstract