Linagliptin prevents atrial electrical and structural remodeling in a canine model of atrial fibrillation

Igarashi, Tazuru; Niwano, Shinichi; Niwano, Hiroe; Yoshizawa, Tomoharu; Nakamura, Hironori; Fukaya, Hidehira; Fujiishi, Tamami; Ishizue, Naruya; Satoh, Akira; Kishihara, Jun; Murakami, Masami; Ako, Junya

doi:10.1007/s00380-018-1170-0

Cited by 10 publications

(7 citation statements)

References 21 publications

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“…Atrial electrical and structural remodeling is the foundation of AF (26), and CaMKII had been reported to mediate the processes associated with atrial contractile function and structural remodeling in AF (27). Yao et al (28) suggested that in pathological states, CAMK2D was associated with heart failure and myocardial hypertrophy, and CAMK2D could play a role in arrhythmia.…”

Section: Discussionmentioning

confidence: 99%

Possible key microRNAs and corresponding molecular mechanisms for atrial fibrillation

et al. 2020

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Possible key microRNAs and corresponding molecular mechanisms for atrial fibrillation Objective: We aimed to find crucial microRNAs (miRNAs) associated with the development of atrial fibrillation (AF), and then try to elucidate the possible molecular mechanisms of miRNAs in AF. Methods: The miRNA microarray, GSE68475, which included 10 right atrial appendage samples from patients with persistent AF and 11 samples from patients with normal sinus rhythm, was used for the analysis. After data preprocessing, differentially expressed miRNAs were screened using limma. Target genes of miRNAs were predicted using miRWalk2.0. We then conducted functional enrichment analyses for miRNA and target genes. Protein-protein interaction (PPI) network and module analyses for target genes were performed. Finally, transcription factors (TFs)-target genes regulatory network was predicted and constructed. Results: Seven genes, including CAMK2D, IGF2R, PPP2R2A, PAX6, POU3F2, YWHAE, and AP2A2, were targeted by TFs. Among these seven genes, CAMK2D (targeted by miR-31-5p), IGF2R (targeted by miR-204-5p), PAX6 (targeted by miR-223-3p), POU3F2 (targeted by miR-204-5p), YWHAE (targeted by miR-31-5p), and AP2A2 (targeted by miR-204-5p) belonged to the top 10 degree genes in the PPI network. Notably, MiR-204-5p, miR-31-5p, and miR-223-3p had more target genes. Besides, CAMK2D was enriched in some pathways, such as adrenergic signaling in cardiomyocytes pathway and cAMP signaling pathway. YWHAE was enriched in the Hippo signaling pathway. Conclusion: miR-31-5p played a crucial role in cardiomyocytes by targeting CAMK2D and YWHAE via cAMP and Hippo signaling pathways. miR-204 was involved in the progression of AF by regulating its target genes IGF2R, POU3F2, and AP2A2. On the other hand, miR-223-3p functioned in AF by targeting PAX6, which was associated with the regulation of apoptosis in AF. This study would provide a theoretical basis and potential therapeutic targets for the treatment of AF.

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Section: Discussionmentioning

confidence: 99%

Possible key microRNAs and corresponding molecular mechanisms for atrial fibrillation

et al. 2020

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“…Block of PAR-1 signaling Oral anti-platelet agent Unknown DPP-4 inhibitors (Lendeckel, 2001;Tremblay, 2014;Wronkowitz, 2014;Gong et al, 2015;Yamamoto, 2015;Chang, 2017;Zhang, 2017;Igarashi, 2018) Sitagliptin, saxagliptin and other gliptins…”

Section: Reduction Of Thrombin Formation (New) Oral Anticoagulantsmentioning

confidence: 99%

“…Also, soluble DPP-4 can activate PAR-2 in vascular smooth muscle cells, leading to production of pro-inflammatory cytokines (Wronkowitz, 2014). Recent work suggested that circulating and/or locally expressed DPP4 plays a role in AF pathogenesis (Lendeckel, 2001;Yamamoto, 2015;Chang, 2017;Zhang, 2017;Igarashi, 2018). A recent observational study revealed that diabetic patients treated with DPP4 inhibitors (gliptins) had a lower risk of AF as compared with patients treated with other drugs (Chang, 2017).…”

Section: Reduction Of Thrombin Formation (New) Oral Anticoagulantsmentioning

confidence: 99%

“…Ectopeptidases such as DPP-4 are expressed in human atrial biopsies from surgical patients, independently from the presence or absence of AF (Lendeckel, 2001). In a canine model of AF due to rapid atrial pacing, linagliptin partially prevented the shortening of atrial refractory period and the slowing of atrial conduction induced by rapid pacing, thus lowering AF inducibility (Igarashi, 2018). In a rabbit heart failure model (ventricular tachypacing), treatment with alogliptin reduced atrial fibrosis and increased atrial capillary density, ultimately reducing the duration of AF episodes (Yamamoto, 2015).…”

Section: Reduction Of Thrombin Formation (New) Oral Anticoagulantsmentioning

confidence: 99%

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Pharmacological Inhibition of Serine Proteases to Reduce Cardiac Inflammation and Fibrosis in Atrial Fibrillation

et al. 2019

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Systemic inflammation correlates with an increased risk of atrial fibrillation (AF) and thrombogenesis. Systemic inflammation alters vessel permeability, allowing inflammatory and immune cell migration toward target organs, including the heart. Among inflammatory cells infiltrating the atria, macrophages and mast cell have recently attracted the interest of basic researchers due to the pathogenic mechanisms triggered by their activation. This chemotactic invasion is likely implicated in shortand long-term changes in cardiac cell-to-cell communication and in triggering fibrous tissue accumulation in the atrial myocardium and electrophysiological rearrangements of atrial cardiomyocytes, thus favoring the onset and progression of AF. Serine proteases are a large and heterogeneous class of proteases involved in several processes that are important for cardiac function and are involved in cardiac diseases, such as (i) coagulation, (ii) fibrinolysis, (iii) extracellular matrix degradation, (iv) activation of receptors (i.e., protease-activated receptors [PPARs]), and (v) modulation of the activity of endogenous signals. The recognition of serine proteases substrates and their involvement in inflammatory/profibrotic mechanisms allowed the identification of novel cardio-protective mechanisms for commonly used drugs that inhibit serine proteases. The aim of this review is to summarize knowledge on the role of inflammation and fibrosis as determinants of AF. Moreover, we will recapitulate current findings on the role of serine proteases in the pathogenesis of AF and the possible beneficial effects of drugs inhibiting serine proteases in reducing the risk of AF through decrease of cardiac inflammation and fibrosis. These drugs include thrombin and factor Xa inhibitors (used as oral anticoagulants), dipeptidyl-peptidase 4 (DPP4) inhibitors, used for type-2 diabetes, as well as novel experimental inhibitors of mast cell chymases.

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“…Cellular electrophysiological studies have shown extensive changes in ion-channels functions leading to disturbed outward and inward currents, including a decreased transient outward K + current (I to ), an increased inward rectifier K + current (I K1 ), and a decreased L-type voltage-gated Ca 2+ current (I Ca,L ), in atria from AT patients [5]. The ionic remodeling in atria disrupted the balance between inward and outward currents and changed the action potential duration and the effective refractory period, which contributed to the pathophysiology of AT [6]. Considering that the Fontan H operation leads to the giant right atrium and a pressure overload of RA, we proposed that the right atrium after the Fontan operation not only caused an anatomic remodeling but also possibly induced an electrical remodeling in ionchannel functions.…”

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confidence: 99%

Ionic mechanisms underlying atrial electrical remodeling after a fontan-style operation in a canine model

Zhou

et al. 2020

Heart Vessels

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Atrial arrhythmia is an important cause of late death in patients after the Fontan-Style operation. However, the detailed electrophysiological characteristics of the post-Fontan atrium and its underlying mechanisms are largely unknown. In this study, we investigated electrophysiological characteristics and the ionic remodeling in the right atrium (RA) of a canine model after the Fontan operation. We performed the operation of RA to pulmonary artery connection to mimic the Fontan operation. We undertook hemodynamic measurements, cardiac electrophysiological studies, and ion current measurements. The expression of ionic channels was analyzed by PCR and western-blotting. Our Fontan model induced RA hypertension, enlarged the size of RA, and increased atrial fibrosis, representing the classic characteristic of Fontan patients. In the Fontan group, the atrial effective refractory period and the active potential duration were reduced, and the atrial tachycardia has been more often to be induced. The electrical conduction mapping showed that the Fontan group reduced the conduction velocity. The Fontan operation significantly down-regulated the expression of KCND3/Kv4.3, CACNA1C/Cav1.2 and SCN5A, but up-regulated the expression of KCNJ2/Kir2.1. Correspondingly, The Fontan operation reduced transient-outward (I to) and L-type Ca2 (I Ca,L) and I Na currents, while increasing the inward-rectifier current (I K1). Thus, the net shortening of the action potential in the post-Fontan atrium is associated with the altered expression of ionic channels which disturbed the balance between inward and outward currents. Taken together, the Fontan operation induces the ionic remodeling, and thus altered electrophysiological characteristics of the right atrium, improving our understanding on the pathophysiology of atrial arrhythmias in Fontan patients.

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Linagliptin prevents atrial electrical and structural remodeling in a canine model of atrial fibrillation

Cited by 10 publications

References 21 publications

Possible key microRNAs and corresponding molecular mechanisms for atrial fibrillation

Possible key microRNAs and corresponding molecular mechanisms for atrial fibrillation

Pharmacological Inhibition of Serine Proteases to Reduce Cardiac Inflammation and Fibrosis in Atrial Fibrillation

Ionic mechanisms underlying atrial electrical remodeling after a fontan-style operation in a canine model

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