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Aminoguanidine prevents fructose-induced deterioration in left ventricular-arterial coupling in Wistar rats.

ABSTRACT: BACKGROUND AND PURPOSE: Aminoguanidine (AG), an inhibitor of advanced glycation endproducts, has been identified as a prominent agent that prevents the fructose-induced arterial stiffening in male Wistar rats. Our aims were to examine whether AG produced benefits on the left ventricular (LV)-arterial coupling in fructose-fed (FF) animals in terms of the ventricular and arterial chamber properties. EXPERIMENTAL APPROACH: Rats given 10% fructose in drinking water (FF) were daily treated with AG (50 mg x kg(-1), i.p.) for 2 weeks and compared with the untreated FF group. In anaesthetised rats, LV pressure and ascending aortic flow signals were recorded to calculate LV end-systolic elastance (E(es), an indicator of myocardial contractility) and effective arterial volume elastance (E(a)). The optimal afterload (Q(load)) determined by the ratio of E(a) to E(es) was used to measure the coupling efficiency between the left ventricle and its vasculature. KEY RESULTS: There was a significant interaction between fructose and AG in their effects on E(a). Fructose loading significantly elevated E(a) and AG prevented the fructose-derived deterioration in arterial chamber elastance. Both fructose and AG affected E(es) and Q(load), and there was an interaction between fructose and AG for these two variables. Both E(es) and Q(load) exhibited a decline with fructose feeding but showed a significant rise after AG treatment in the FF rats. CONCLUSIONS AND IMPLICATIONS: AG prevented not only the contractile dysfunction of the heart caused by fructose loading, but also the fructose-induced deterioration in matching left ventricular function to the arterial system.

SUBMITTER: Chang KC

PROVIDER: S-EPMC2013974 | biostudies-other | 2007 Jun

REPOSITORIES: biostudies-other

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Project description:BackgroundPatients with dilated cardiomyopathy, increased ventricular volume, pressure overload or dysynergistic ventricular contraction and relaxation are susceptible to develop serious ventricular arrhythmias (VA). These phenomena are primarily based on a theory of mechanoelectric feedback, which reflects mechanical changes that produce alterations in electrical activity. However, very few systematic studies have provided evidence of the preventive effects of artemisinin (ART) on VA in response to left ventricle (LV) afterload increases. MicroRNAs (miRNAs) are endogenous small non-coding RNAs that regulate expression of multiple genes by suppressing mRNAs post-transcriptionally.AimsThe aims of this study were to investigate preventive effects of ART on mechanical VA and the underling molecular mechanisms of differentially expressed miRNAs (DEMs).MethodsFor the study, 70 male Wistar rats were randomly divided into seven groups: group 1 was a control group (sham surgery); group 2 was a model group that underwent transverse aortic constriction (TAC) surgery; groups 3, 4, 5 and 6 were administered ART 75, 150, 300 and 600 mg/kg before TAC surgery, respectively; and group 7 was administered verapamil (VER) 1 mg/kg before TAC surgery. A ventricular arrhythmia score (VAS) was calculated to evaluate preventive effects of ART and VER on mechanical VA. The high throughput sequencing-based approach provided DEMs that were altered by ART pretreatment between group 2 and group 4. All predicted mRNAs of DEMs were enriched by gene ontology (GO) and Kyoto Encyclopedia annotation of Genes and Genomes (KEGG) databases. These DEMs were validated by a real time quantitative polymerase chain reaction (RT-qPCR).ResultsThe average VASs of groups 3, 4, 5, 6 and 7 were significantly reduced compared with those of group 2 (2.70 ± 0.48, 1.70 ± 0.95, 2.80 ± 0.79, 2.60 ± 0.97, 1.40 ± 0.52, vs 3.70 ± 0.67, p < 0.01, respectively). The three top GO terms were neuron projection, organ morphogenesis and protein domain specific binding. KEGG enrichment of the 16 DEMs revealed that MAPK, Wnt and Hippo signaling pathways were likely to play a substantial role in the preventive effects of ART on mechanical VA in response to LV afterload increases. All candidate DEMs with the exception of rno-miR-370-3p, rno-miR-6319, rno-miR-21-3p and rno-miR-204-5p showed high expression levels validated by RT-qPCR.ConclusionsArtemisinin could prevent mechanical VA in response to LV afterload increases. Validated DEMs could be biomarkers and therapeutic targets of ART regarding its prevention of VA induced by pressure overload. The KEGG pathway and GO annotation analyses of the target mRNAs could indicate the potential functions of candidate DEMs. These results will help to elucidate the functional and regulatory roles of candidate DEMs associated with antiarrhythmic effects of ART.

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Aminoguanidine prevents fructose-induced deterioration in left ventricular-arterial coupling in Wistar rats.

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