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Arrhythmia refers to irregularities in the rate and rhythm of the heart, with symptoms spanning from mild palpitations to life-threatening arrhythmias and sudden cardiac death (SCD). The complex molecular nature of arrhythmias complicates the selection of appropriate treatment. Current therapies involve the use of antiarrhythmic drugs (class I-IV) with limited efficacy and dangerous side effects and implantable pacemakers and cardioverter-defibrillators with hardware-related complications and inappropriate shocks. The number of novel antiarrhythmic drug in the development pipeline has decreased substantially during the last decade and underscores uncertainties regarding future developments in this field. Consequently, arrhythmia treatment poses significant challenges, prompting the need for alternative approaches. Remarkably, innovative drug discovery and development technologies show promise in helping advance antiarrhythmic therapies. Here, we review unique characteristics and the transformative potential of emerging technologies that offer unprecedented opportunities for transitioning from traditional antiarrhythmics to next-generation therapies. We assess stem cell technology, emphasizing the utility of innovative cell profiling using multi-omics, high-throughput screening, and advanced computational modeling in developing treatments tailored precisely to individual genetic and physiological profiles. We offer insights into gene therapy, peptide and peptibody approaches for drug delivery. We finally discuss potential strengths and weaknesses of such techniques in reducing adverse effects and enhancing overall treatment outcomes, leading to more effective, specific, and safer therapies. Altogether, this comprehensive overview introduces innovative avenues for personalized rhythm therapy, with particular emphasis on drug discovery, aiming to advance the arrhythmia treatment landscape and the prevention of SCD. Significance Statement Arrhythmias and sudden cardiac death account for 15-20% of deaths worldwide. However, current antiarrhythmic therapies are ineffective and with dangerous side effects. Here, we review the field of arrhythmia treatment underscoring the slow progress in advancing the cardiac rhythm therapy pipeline and the uncertainties regarding evolution of this field. We provide information on how emerging technological and experimental tools can help accelerate progress and address the limitations of antiarrhythmic drug discovery.

Cancers and cardiovascular diseases are the top two causes of death in the United States. Over the past decades, novel therapies have slowed the cancer mortality rate, yet cardiac failures have risen due to the toxicity of cancer treatments. The mechanisms behind this relationship are poorly understood and it is crucial that we properly treat patients at risk of developing cardiac failure in response to cancer treatments. Currently, we rely on early-stage biomarkers of inflammation and angiogenesis to detect cardiotoxicity before it becomes irreversible. Identification of such biomarkers allows healthcare professionals to decrease the adverse effects of cancer therapies. Angiogenesis and inflammation have a systemic influence on the heart and vasculature following cancer therapy. In the field of cardio-oncology, there has been a recent emphasis on gender and racial disparities in cardiotoxicity and the impact of these disparities on disease outcomes, but there is a scarcity of data on how cardiotoxicity varies across diverse populations. Here, we will discuss how current markers of angiogenesis and inflammation induced by cancer therapy are related to disparities in cardiovascular health., Competing Interests: Declaration of competing interest The authors claim no declaration of interest. None of the authors affiliated with this review have any declaration of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Familial dilated cardiomyopathy (DCM) is among the most prevalent forms of inherited heart disease. Here, two human-induced pluripotent stem cell (iPSC) lines were generated from peripheral blood mononuclear cells (PBMCs) from DCM patients carrying different mutations in the phospholamban encoding-gene (PLN). Both iPSC lines exhibited normal morphology, karyotype, pluripotency marker expression, and differentiation into the three germ layers. These patient-specific iPSC lines serve as valuable in vitro models for DCM pathology caused by PLN mutations., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

The dysregulation of K + channels is a hallmark of pulmonary arterial hypertension (PAH). Herein, the channelome was analyzed in lungs of patients with PAH in a public transcriptomic database. Sixty six (46%) mRNA encoding cationic channels were dysregulated in PAH with most of them downregulated (83%). The principal component analysis indicated that dysregulated cationic channel expression is a signature of the disease. Changes were very similar in idiopathic, connective tissue disease and congenital heart disease associated PAH. This analysis 1) is in agreement with the widely recognized pathophysiological role of TASK1 and K V 1.5, 2) supports previous preliminary reports pointing to the dysregulation of several K + channels including the downregulation of K V 1.1, K V 1.4, K V 1.6, K V 7.1, K V 7.4, K V 9.3 and TWIK2 and the upregulation of K Ca 1.1 and 3) points to other cationic channels dysregulated such as Kv7.3, TALK2, Ca V 1 and TRPV4 which might play a pathophysiological role in PAH. The significance of other changes found in Na + and TRP channels remains to be investigated., (© 2021. The Author(s).)

Background: Vitamin D (vitD) deficiency is highly prevalent in patients with pulmonary arterial hypertension (PAH). Moreover, PAH-patients with lower levels of vitD have worse prognosis. We hypothesize that recovering optimal levels of vitD in an animal model of PAH previously depleted of vitD improves the hemodynamics, the endothelial dysfunction and the ionic remodeling. Methods: Male Wistar rats were fed a vitD-free diet for five weeks and then received a single dose of Su5416 (20 mg/Kg) and were exposed to vitD-free diet and chronic hypoxia (10% O 2 ) for three weeks to induce PAH. Following this, vitD deficient rats with PAH were housed in room air and randomly divided into two groups: (a) continued on vitD-free diet or (b) received an oral dose of 100,000 IU/Kg of vitD plus standard diet for three weeks. Hemodynamics, pulmonary vascular remodeling, pulmonary arterial contractility, and K + currents were analyzed. Results: Recovering optimal levels of vitD improved endothelial function, measured by an increase in the endothelium-dependent vasodilator response to acetylcholine. It also increased the activity of TASK-1 potassium channels. However, vitD supplementation did not reduce pulmonary pressure and did not ameliorate pulmonary vascular remodeling and right ventricle hypertrophy. Conclusions: Altogether, these data suggest that in animals with PAH and severe deficit of vitD, restoring vitD levels to an optimal range partially improves some pathophysiological features of PAH.

Current approved therapies for pulmonary hypertension (PH) aim to restore the balance between endothelial mediators in the pulmonary circulation. These drugs may exert vasodilator effects on poorly oxygenated vessels. This may lead to the derivation of blood perfusion towards low ventilated alveoli, i.e., producing ventilation-perfusion mismatch, with detrimental effects on gas exchange. The aim of this study is to analyze the oxygen-sensitivity in vitro of 25 drugs currently used or potentially useful for PH. Additionally, the study analyses the effectiveness of these vasodilators in the pulmonary vs the systemic vessels. Vasodilator responses were recorded in pulmonary arteries (PA) and mesenteric arteries (MA) from rats and in human PA in a wire myograph under different oxygen concentrations. None of the studied drugs showed oxygen selectivity, being equally or more effective as vasodilators under conditions of low oxygen as compared to high oxygen levels. The drugs studied showed low pulmonary selectivity, being equally or more effective as vasodilators in systemic than in PA. A similar behavior was observed for the members within each drug family. In conclusion, none of the drugs showed optimal vasodilator profile, which may limit their therapeutic efficacy in PH.

Objective: The SMIT1 (sodium:myo-inositol transporter 1) regulates myo-inositol movement into cells and responses to hypertonic stimuli. Alteration of myo-inositol levels has been associated with several diseases, including hypertension, but there is no evidence of a functional role of SMIT1 in the vasculature. Recent evidence showed that in the nervous system SMIT1 interacted and modulated the function of members of the Kv7 family of voltage-gated potassium channels, which are also expressed in the vasculature where they regulate arterial contractility. Therefore, in this study, we evaluated whether SMIT1 was functionally relevant in arterial smooth muscle. Approach and Results: Immunofluorescence and polymerase chain reaction experiments revealed that SMIT1 was expressed in rat renal and mesenteric vascular smooth muscle cells. Isometric tension recordings showed that incubation of renal arteries with raffinose and myo-inositol (which increases SMIT1 expression) reduced the contractile responses to methoxamine, an effect that was abolished by preincubation with the pan-Kv7 blocker linopirdine and by molecular knockdown of Kv7.4 and Kv7.5. Knockdown of SMIT1 increased the contraction of renal arteries induced by methoxamine, impaired the response to the Kv7.2-Kv7.5 activator ML213 but did not interfere with the relaxant responses induced by openers of other potassium channels. Proximity ligation assay showed that SMIT1 interacted with heteromeric channels formed by Kv7.4 and Kv7.5 proteins in both renal and mesenteric vascular smooth muscle cells. Patch-clamp experiments showed that incubation with raffinose plus myo-inositol increased Kv7 currents in vascular smooth muscle cells., Conclusions: SMIT1 protein is expressed in vascular smooth muscle cells where it modulates arterial contractility through an association with Kv7.4/Kv7.5 heteromers.

Vitamin D (VitD) receptor regulates the expression of several genes involved in signaling pathways affected in pulmonary hypertension (PH). VitD deficiency is highly prevalent in PH, and low levels are associated with poor prognosis. We investigated if VitD deficiency may predispose to or exacerbate PH. Male Wistar rats were fed with a standard or a VitD-free diet for 5 wk. Next, rats were further divided into controls or PH, which was induced by a single dose of Su-5416 (20 mg/kg) and exposure to hypoxia (10% O 2 ) for 2 wk. VitD deficiency had no effect on pulmonary pressure in normoxic rats, indicating that, by itself, it does not trigger PH. However, it induced several moderate but significant changes characteristic of PH in the pulmonary arteries, such as increased muscularization, endothelial dysfunction, increased survivin, and reduced bone morphogenetic protein ( Bmp ) 4 , Bmp6 , DNA damage-inducible transcript 4 , and K + two - pore domain channel subfamily K member 3 ( Kcnk3 ) expression. Myocytes isolated from pulmonary arteries from VitD-deficient rats had a reduced whole voltage-dependent potassium current density and acid-sensitive (TASK-like) potassium currents. In rats with PH induced by Su-5416 plus hypoxia, VitD-free diet induced a modest increase in pulmonary pressure, worsened endothelial function, increased the hyperreactivity to serotonin, arterial muscularization, decreased total and TASK-1 potassium currents, and further depolarized the pulmonary artery smooth muscle cell membrane. In human pulmonary artery smooth muscle cells from controls and patients with PH, the active form of VitD calcitriol significantly increased KCNK3 mRNA expression. Altogether, these data strongly suggest that the deficit in VitD induces pulmonary vascular dysfunction.

Lung diseases constitute a global health concern causing disability. According to WHO in 2016, respiratory diseases accounted for 24% of world population mortality, the second cause of death after cardiovascular diseases. The Kv7 channels family is a group of voltage-dependent K + channels (Kv) encoded by KCNQ genes that are involved in various physiological functions in numerous cell types, especially, cardiac myocytes, smooth muscle cells, neurons, and epithelial cells. Kv7 channel α-subunits are regulated by KCNE1-5 ancillary β-subunits, which modulate several characteristics of Kv7 channels such as biophysical properties, cell-location, channel trafficking, and pharmacological sensitivity. Kv7 channels are mainly expressed in two large groups of lung tissues: pulmonary arteries (PAs) and bronchial tubes. In PA, Kv7 channels are expressed in pulmonary artery smooth muscle cells (PASMCs); while in the airway (trachea, bronchus, and bronchioles), Kv7 channels are expressed in airway smooth muscle cells (ASMCs), airway epithelial cells (AEPs), and vagal airway C-fibers (VACFs). The functional role of Kv7 channels may vary depending on the cell type. Several studies have demonstrated that the impairment of Kv7 channel has a strong impact on pulmonary physiology contributing to the pathophysiology of different respiratory diseases such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, chronic coughing, lung cancer, and pulmonary hypertension. Kv7 channels are now recognized as playing relevant physiological roles in many tissues, which have encouraged the search for Kv7 channel modulators with potential therapeutic use in many diseases including those affecting the lung. Modulation of Kv7 channels has been proposed to provide beneficial effects in a number of lung conditions. Therefore, Kv7 channel openers/enhancers or drugs acting partly through these channels have been proposed as bronchodilators, expectorants, antitussives, chemotherapeutics and pulmonary vasodilators., (Copyright © 2020 Mondejar-Parreño, Perez-Vizcaino and Cogolludo.)

Introduction : Epidemiological studies suggest a relationship between vitamin D deficiency and cardiovascular and respiratory diseases. However, whether total, bioavailable, and/or free vitamin D levels have a prognostic role in pulmonary arterial hypertension (PAH) is unknown. We aimed to determine total, bioavailable, and free 25-hydroxy-vitamin D (25(OH)vitD) plasma levels and their prognostic value in PAH patients. Methods : In total, 67 samples of plasma from Spanish patients with idiopathic, heritable, or drug-induced PAH were obtained from the Spanish PH Biobank and compared to a cohort of 100 healthy subjects. Clinical parameters were obtained from the Spanish Registry of PAH (REHAP). Results : Seventy percent of PAH patients had severe vitamin D deficiency (total 25(OH)vitD < 10 ng/mL) and secondary hyperparathyroidism. PAH patients with total 25(OH)vitD plasma above the median of this cohort (7.17 ng/mL) had better functional class and higher 6-min walking distance and TAPSE (tricuspid annular plane systolic excursion). The main outcome measure of survival was significantly increased in these patients (age-adjusted hazard ratio: 5.40 (95% confidence interval: 2.88 to 10.12)). Vitamin D-binding protein (DBP) and albumin plasma levels were downregulated in PAH. Bioavailable 25(OH)vitD was decreased in PAH patients compared to the control cohort. Lower levels of bioavailable 25(OH)vitD (<0.91 ng/mL) were associated with more advanced functional class, lower exercise capacity, and higher risk of mortality. Free 25(OH)vitD did not change in PAH; however, lower free 25(OH)vitD (<1.53 pg/mL) values were also associated with high risk of mortality. Conclusions : Vitamin D deficiency is highly prevalent in PAH, and low levels of total 25(OH)vitD were associated with poor prognosis., Competing Interests: The authors declare no conflicts of interest regarding the present study.

Endothelial dysfunction plays a central role in the pathophysiology of pulmonary arterial hypertension (PAH). MicroRNAs (miRNAs) are small single-strand and non-coding RNAs that negatively regulate gene function by binding to the 3'-untranslated region (3'-UTR) of specific mRNAs. microRNA-1 (miR-1) is upregulated in plasma from idiopathic PAH patients and in lungs from an experimental model of PAH. However, the role of miRNA-1 on endothelial dysfunction is unknown. The aim of this study was to analyze the effects of miR-1 on endothelial function in rat pulmonary arteries (PA). Endothelial function was studied in PA from PAH or healthy animals and mounted in a wire myograph. Some PA from control animals were transfected with miR-1 or scramble miR. Superoxide anion production by miR-1 was quantified by dihydroethidium (DHE) fluorescence in rat PA smooth muscle cells (PASMC). Bioinformatic analysis identified superoxide dismutase-1 (SOD1), connexin-43 (Cx43), caveolin 2 (CAV2) and Krüppel-like factor 4 (KLF4) as potential targets of miR-1. The expression of SOD1, Cx43, CAV2, and KLF4 was determined by qRT-PCR and western blot in PASMC. PA incubated with miR-1 presented decreased endothelium-dependent relaxation to acetylcholine. We also found an increase in the production of O 2 - and decreased expression of SOD1, Cx43, CAV2, and KLF4 in PASMC induced by miR-1, which may contribute to endothelial dysfunction. In conclusion, these data indicate that miR-1 induces endothelial dysfunction, suggesting a pathophysiological role in PAH.

Key Points: The expression of miR-1 is increased in lungs from the Hyp/Su5416 PAH rat model. Pulmonary artery smooth muscle cells from this animal model are more depolarized and show decreased expression and activity of voltage-dependent potassium channel (Kv)1.5. miR-1 directly targets Kv1.5 channels, reduces Kv1.5 activity and induces membrane depolarization. Antagomir-1 prevents Kv1.5 channel downregulation and the depolarization induced by hypoxia/Su5416 exposition., Abstract: Impairment of the voltage-dependent potassium channel (Kv) plays a central role in the development of cardiovascular diseases, including pulmonary arterial hypertension (PAH). MicroRNAs are non-coding RNAs that regulate gene expression by binding to the 3'-untranslated region region of specific mRNAs. The present study aimed to analyse the effects of miR-1 on Kv channel function in pulmonary arteries (PA). Kv channel activity was studied in PA from healthy animals transfected with miR-1 or scrambled-miR. Kv currents were studied using the whole-cell configuration of the patch clamp technique. The characterization of the Kv1.5 currents was performed with the selective inhibitor DPO-1. miR-1 expression was increased and Kv1.5 channels were decreased in lungs from a rat model of PAH induced by hypoxia and Su5416. miR-1 transfection increased cell capacitance, reduced Kv1.5 currents and induced membrane depolarization in isolated pulmonary artery smooth muscle cells. A luciferase reporter assay indicated that KCNA5, which encodes Kv1.5 channels, is a direct target gene of miR-1. Incubation of PA with Su5416 and hypoxia (3% O 2 ) increased miR-1 and induced a decline in Kv1.5 currents, which was prevented by antagomiR-1. In conclusion, these data indicate that miR-1 induces pulmonary artery smooth muscle cell hypertrophy and reduces the activity and expression of Kv channels, suggesting a pathophysiological role in PAH., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Diabetes is a very strong predictor of chronic systemic vascular diseases and acute cardiovascular events. Recently, associations between metabolic disorders and pulmonary hypertension have also been reported in both humans and animal models. In order to get some further insight into the relationship of pulmonary hypertension with obesity, insulin resistance and hyperglycemia, herein we have used the Zucker diabetic fatty rats (ZDF/clr-lepr fa) at 20 weeks fed a standard diet and compared to their lean Zucker littermates (ZL). ZDF rats were obese, had elevated plasma glucose levels and insulin resistance, i.e. a clinically relevant model of type 2 diabetes. They presented elevated systolic, diastolic and mean pulmonary arterial pressures and a parallel increase in the Fulton index. Systemic arterial pressures were also increased but the left ventricle plus septum weight was similar in both groups and the heart rate was reduced. Wall media thickening was observed in the small pulmonary arteries from the ZDF rats. Isolated pulmonary arteries mounted in a wire myograph showed similar vasoconstrictor responses to phenylephrine and 5-HT and similar responses to the endothelium-dependent vasodilator acetylcholine. However, the iNOS inhibitor 1400W enhanced the vasoconstrictor responses in ZDF but not in ZL rats. The protein expression of eNOS and iNOS was not significantly different in the lungs of the two groups. The lung expression of Bmpr2 mRNA was downregulated. However, the mRNA expression of Kcna5, Kcnk3, Kcnq1, Kcnq4 or Kcnq5, which encode for the potassium channels Kv1.5, TASK-1, Kv7.1, Kv7.4 and Kv7.5, respectively, was similar in ZL and ZDF rats. In conclusion, ZDF rats show increased pulmonary arterial pressure, right ventricular hypertrophy, pulmonary arterial medial thickening and downregulated lung Bmpr2 despite leptin resistance. These changes were mild but are consistent with the view that diabetes is a risk factor for pulmonary hypertension., Competing Interests: The authors have declared that no competing interests exist.

Human immunodeficiency virus (HIV) infection is an established risk factor for pulmonary arterial hypertension (PAH); however, the pathogenesis of HIV-related PAH remains unclear. Since K + channel dysfunction is a common marker in most forms of PAH, our aim was to analyze whether the expression of HIV proteins is associated with impairment of K + channel function in the pulmonary vascular bed. HIV transgenic mice (Tg26) expressing seven of the nine HIV viral proteins and wild-type (WT) mice were used. Hemodynamic assessment was performed by echocardiography and catheterization. Vascular reactivity was studied in endothelium-intact pulmonary arteries. K + currents were recorded in freshly isolated pulmonary artery smooth muscle cells (PASMC) using the patch-clamp technique. Gene expression was assessed using quantitative RT-PCR. PASMC from Tg26 mice had reduced K + currents and were more depolarized than those from WT. Whereas voltage-gated K + channel 1.5 (Kv1.5) currents were preserved, pH-sensitive noninactivating background currents ( I KN ) were nearly abolished in PASMC from Tg26 mice. Tg26 mice had reduced lung expression of Kv7.1 and Kv7.4 channels and decreased responses to the Kv7.1 channel activator L-364,373 assessed by vascular reactivity and patch-clamp experimental approaches. Although we found pulmonary vascular remodeling and endothelial dysfunction in Tg26 mice, this was not accompanied by changes in hemodynamic parameters. In conclusion, the expression of HIV proteins in vivo impairs pH-sensitive I KN and Kv7 currents. This negative impact of HIV proteins in K + channels was not sufficient to induce PAH, at least in mice, but may play a permissive or accessory role in the pathophysiology of HIV-associated PAH.

We have analysed whether pulmonary arterial hypertension (PAH) alters the rat faecal microbiota. Wistar rats were injected with the VEGF receptor antagonist SU5416 (20 mg/kg s.c.) and followed for 2 weeks kept in hypoxia (10% O 2 , PAH) or injected with vehicle and kept in normoxia (controls). Faecal samples were obtained and microbiome composition was determined by 16S rRNA gene sequencing and bioinformatic analysis. No effect of PAH on the global microbiome was found (α- or β-diversity). However, PAH-exposed rats showed gut dysbiosis as indicated by a taxonomy-based analysis. Specifically, PAH rats had a three-fold increase in Firmicutes-to-Bacteroidetes ratio. Within the Firmicutes phylum, there were no large changes in the relative abundance of the bacterial families in PAH. Among Bacteroidetes, all families were less abundant in PAH. A clear separation was observed between the control and PAH clusters based on short chain fatty acid producing bacterial genera. Moreover, acetate was reduced in the serum of PAH rats. In conclusion, faecal microbiota composition is altered as a result of PAH. This misbalanced bacterial ecosystem might in turn play a pathophysiological role in PAH by altering the immunologic, hormonal and metabolic homeostasis.

Introduction: Current treatment with vasodilators for pulmonary hypertension associated with respiratory diseases is limited by their inhibitory effect on hypoxic pulmonary vasoconstriction (HPV) and uncoupling effects on ventilation-perfusion (V'/Q'). Hypoxia is also a well-known modulator of the nitric oxide (NO) pathway, and may therefore differentially affect the responses to phosphodiesterase 5 (PDE5) inhibitors and soluble guanylyl cyclase (sGC) stimulators. So far, the effects of the sGC stimulator riociguat on HPV have been poorly characterized., Materials and Methods: Contraction was recorded in pulmonary arteries (PA) in a wire myograph. Anesthetized rats were catheterized to record PA pressure. Ventilation and perfusion were analyzed by micro-CT-SPECT images in rats with pulmonary fibrosis induced by bleomycin., Results: The PDE5 inhibitor sildenafil and the sGC stimulator riociguat similarly inhibited HPV in vitro and in vivo. Riociguat was more effective as vasodilator in isolated rat and human PA than sildenafil. Riociguat was ≈3-fold more potent under hypoxic conditions and it markedly inhibited HPV in vivo at a dose that barely affected the thromboxane A2 (TXA2) mimetic U46619-induced pressor responses. Pulmonary fibrosis was associated with V'/Q' uncoupling and riociguat did not affect the V'/Q' ratio., Conclusion: PDE5 inhibitors and sGC stimulators show a different vasodilator profile. Riociguat was highly effective and potentiated by hypoxia in rat and human PA. In vivo, riociguat preferentially inhibited hypoxic than non-hypoxic vasoconstriction. However, it did not worsen V'/Q' coupling in a rat model of pulmonary fibrosis.

PPARβ/δ activation protects against endothelial dysfunction in diabetic models. Elevated glucose is known to impair cAMP-induced relaxation and Kv channel function in coronary arteries (CA). Herein, we aimed to analyse the possible protective effects of the PPARβ/δ agonist GW0742 on the hyperglycaemic-induced impairment of cAMP-induced relaxation and Kv channel function in rat CA. As compared with low glucose (LG), incubation under high glucose (HG) conditions attenuated the relaxation induced by the adenylate cyclase activator forskolin in CA and this was prevented by GW0742. The protective effect of GW0742 was supressed by a PPARβ/δ antagonist. In myocytes isolated from CA under LG, forskolin enhanced Kv currents and induced hyperpolarization. In contrast, when CA were incubated with HG, Kv currents were diminished and the electrophysiological effects of forskolin were abolished. These deleterious effects were prevented by GW0742. The protective effects of GW0742 on forskolin-induced relaxation and Kv channel function were confirmed in CA from type-1 diabetic rats. In addition, the differences in the relaxation induced by forskolin in CA incubated under LG, HG or HG + GW0742 were abolished by the Kv7 channel inhibitor XE991. Accordingly, GW0742 prevented the down-regulation of Kv7 channels induced by HG. Finally, the preventive effect of GW0742 on oxidative stress and cAMP-induced relaxation were overcome by the pyruvate dehydrogenase kinase 4 (PDK4) inhibitor dichloroacetate (DCA). Our results reveal that the PPARβ/δ agonist GW0742 prevents the impairment of the cAMP-mediated relaxation in CA under HG. This protective effect was associated with induction of PDK4, attenuation of oxidative stress and preservation of Kv7 channel function., (© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.)