Electrical Conduction System Remodeling in Streptozotocin-Induced Diabetes Mellitus Rat Heart

Zhang, Yu; Wang, Yanwen; Yanni, Joseph; Qureshi, M. A.; Logantha, Sunil Jit R. J.; Kassab, Sarah; Boyett, Mark R.; Gardiner, Natalie J.; Sun, Hong; Howarth, Frank Christopher; Dobrzynski, Halina

doi:10.3389/fphys.2019.00826

Cited by 28 publications

(30 citation statements)

References 72 publications

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“…Genes underlying familial and acquired sick sinus syndrome. Familial sick sinus syndrome has been linked to mutations in Hcn4 91 , and acquired sick sinus syndrome in ageing 92 , heart failure 93 , atrial fibrillation 94 , diabetes 95 , pulmonary hypertension 96 and even athletes 11 has been linked to a downregulation of Hcn4. If there is a day-night rhythm in Hcn4 (P = 0.072), this may impact sick sinus syndrome.…”

Section: Discussionmentioning

confidence: 99%

RNAseq shows an all-pervasive day-night rhythm in the transcriptome of the pacemaker of the heart

Wang

Anderson

Dobrzynski

et al. 2021

Sci Rep

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Physiological systems vary in a day-night manner anticipating increased demand at a particular time. Heart is no exception. Cardiac output is primarily determined by heart rate and unsurprisingly this varies in a day-night manner and is higher during the day in the human (anticipating increased day-time demand). Although this is attributed to a day-night rhythm in post-translational ion channel regulation in the heart’s pacemaker, the sinus node, by the autonomic nervous system, we investigated whether there is a day-night rhythm in transcription. RNAseq revealed that ~ 44% of the sinus node transcriptome (7134 of 16,387 transcripts) has a significant day-night rhythm. The data revealed the oscillating components of an intrinsic circadian clock. Presumably this clock (or perhaps the master circadian clock in the suprachiasmatic nucleus) is responsible for the rhythm observed in the transcriptional machinery, which in turn is responsible for the rhythm observed in the transcriptome. For example, there is a rhythm in transcripts responsible for the two principal pacemaker mechanisms (membrane and Ca2+ clocks), transcripts responsible for receptors and signalling pathways known to control pacemaking, transcripts from genes identified by GWAS as determinants of resting heart rate, and transcripts from genes responsible for familial and acquired sick sinus syndrome.

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Section: Discussionmentioning

confidence: 99%

RNAseq shows an all-pervasive day-night rhythm in the transcriptome of the pacemaker of the heart

Wang

Anderson

Dobrzynski

et al. 2021

Sci Rep

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“…Similarly, a decrease of HCN was found in the atria of metabolic murine model of mitochondrial dysfunction [ 19 ] and in sinoatrial node of Goto-Kakizaki type 2 diabetic rats [ 39 ]. Importantly, HCN downregulation was reported also in pacemaker cells [ 20 ], in sinoatrial node [ 20 ] and whole cardiac conduction system [ 40 ] of rats with type 1 diabetes mellitus induced by STZ manifesting in lower intrinsic heart rate, a lengthened sinoatrial conduction time and rate-corrected maximal sinoatrial node recovery time in vivo as well as a longer cycle length in vitro [ 20 ]. Also, knock out mouse models lacking Hcn2 or Hcn4 channels exhibit sinoatrial heart disturbances without reports of ventricular electric abnormalities [ 8 , 9 ] suggesting different roles of HCN channels in ventricles.…”

Section: Discussionmentioning

confidence: 99%

Isolated downregulation of HCN2 in ventricles of rats with streptozotocin-induced diabetic cardiomyopathy

Hadova

Kráľová

Doka

et al. 2021

BMC Cardiovasc Disord

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Background In spite of disrupted repolarization of diabetic heart, some studies report less tendency of diabetic heart to develop ventricular arrhythmias suggesting effective compensatory mechanism. We hypothesized that myocardial alterations in HCN2 and HCN4 channels occur under hyperglycaemia. Methods Diabetes was induced in rats using a single injection of streptozotocin (STZ; 55 mg/kg body weight, i.p.). Basal ECG was measured. Expression of mRNA for HCN channels, potassium channels and microRNA 1 and 133a were measured in ventricular tissues. Protein expression of HCN2 channel isoform was assessed in five different regions of the heart by western blotting. Differentiated H9c2 cell line was used to examine HCN channels expression under hyperglycaemia in vitro. Results Six weeks after STZ administration, heart rate was reduced, QRS complex duration, QT interval and T-wave were prolonged in diabetic rats compared to controls. mRNA and protein expressions of HCN2 decreased exclusively in the ventricles of diabetic rats. HCN2 expression levels in atria of STZ rats and H9c2 cells treated with excess of glucose were not changed. MicroRNA levels were stable in STZ rat hearts. We found significantly decreased mRNA levels of several potassium channels participating in repolarization, namely Kcnd2 (Ito1), Kcnh2 (IKr), Kcnq1 (IKs) and Kcnj11 (IKATP). Conclusions This result together with downregulated HCN2 channels suggest that HCN channels might be an integral part of ventricular electric remodelling and might play a role in cardiac repolarization projected in altered arrhythmogenic profile of diabetic heart.

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“…Zhang et al reported that the family Bacteroidaceae was dysregulated in a diabetic mouse model [38]. Previous studies have shown that the abundance levels of Lactobacillus and Allobaculum, bene cial bacteria that can directly protect intestinal barrier function, are reduced in diabetic animal models [39,40].…”

Section: Discussionmentioning

confidence: 99%

Pyridostigmine Protects Against Diabetic Cardiomyopathy by Regulating Gut Microbiota and Branched-Chain Amino Acid Catabolism to Attenuate Mitochondria Dysfunction

Yang

Zhao

et al. 2020

Preprint

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Background: Recent studies have reported that disruption of gut microbes and their metabolites is associated with diabetic cardiomyopathy, but the mechanism by which gut microbes improve diabetic cardiomyopathy remains unclear. Method: Male C57BL/6J mice with high-fat diet and streptozotocin-induced diabetic cardiomyopathy were studied in comparison with control littermates. Diabetic mice were either untreated or subjected to daily intragastric of pyridostigmine. After 10 weeks of hyperglycaemia, vagus activity, cardiac function and cardiac structure were measured by heart rate variability assessment, echocardiography, and immunohistochemistry. The intestinal barrier and gut microbiota were evaluated by fluorescence in situ hybridization and high-throughput sequencing. Additionally, plasma and cardiac branched-chain amino acid (BCAA) distribution and cardiac BCAA catabolism were determined. The structure and respiratory function of mitochondria were measured to assess cardiac mitochondria performance. Results: Intestinal permeability and tight junctions were impaired, bacterial translocation was increased, vagal activity was decreased in mice with diabetic cardiomyopathy mice. Additionally, gut microbes in mice with diabetic cardiomyopathy were disrupted, especially key microbes related to diabetes and BCAA production. Pyridostigmine, which reversibly inhibits cholinesterase to improve autonomic imbalance, enhanced vagus nerve activity, improved insulin resistance and cardiac damage, and alleviated intestinal barrier injury and gut microbiota disruption. Specifically, pyridostigmine decreased the abundance of diabetes-non-protective microbes and increased that of diabetes-protective microbes and BCAA-producing microbes. Pyridostigmine decreased cardiac BCAA concentrations by impairing gut microbe-mediated BCAA production. Furthermore, pyridostigmine upregulated BCAT2 and PP2Cm expression and decreased P-BCKDHA/BCKDHA and BCKDK expression, thus improving cardiac BCAA catabolism. Interestingly, the mitochondrial structural and functional disruption in mice with diabetic cardiomyopathy was attenuated after pyridostigmine administration, which may indicate one of the mechanisms by which BCAAs reduce cardiac damage. Conclusions: In conclusion, intestinal barrier, gut microbiota and vagal activity were impaired in mice with diabetic cardiomyopathy. Pyridostigmine ameliorated insulin resistance and cardiomyopathy, with an effect related to regulated gut microbes and its metabolite BCAA catabolism to attenuate mitochondria dysfunction of heart. These results provide novel insights for the development of a therapeutic strategy for diabetes-induced cardiac damage that targets gut microbes and BCAA catabolism.

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Electrical Conduction System Remodeling in Streptozotocin-Induced Diabetes Mellitus Rat Heart

Cited by 28 publications

References 72 publications

RNAseq shows an all-pervasive day-night rhythm in the transcriptome of the pacemaker of the heart

RNAseq shows an all-pervasive day-night rhythm in the transcriptome of the pacemaker of the heart

Isolated downregulation of HCN2 in ventricles of rats with streptozotocin-induced diabetic cardiomyopathy

Pyridostigmine Protects Against Diabetic Cardiomyopathy by Regulating Gut Microbiota and Branched-Chain Amino Acid Catabolism to Attenuate Mitochondria Dysfunction

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