Complex consequences of Cantu syndrome SUR2 variant R1154Q in genetically modified mice

Zhang, Haixia; Hanson, Alex; Almeida, Tobias Scherf de; Emfinger, Christopher H.; McClenaghan, Conor; Harter, Theresa; Yan, Zihan; Cooper, Paige; Brown, George; Arakel, Eric Clement; Mecham, Robert P.; Kovács, Atilla; Halabi, Carmen M.; Schwappach, Blanche; Remedi, Marı́a S.; Nichols, Colin G.

doi:10.1172/jci.insight.145934

Cited by 11 publications

(21 citation statements)

References 51 publications

(97 reference statements)

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“…Interestingly, some patients with Cantu syndrome also develop pulmonary hypertension ( 43 – 46 ). Twelve different ABCC9 mutations are gain-of-function ( 43 ) or LOF-of-function mutations ( 47 ). The pathophysiological mechanism involving the development of PH is complex, suggesting that the constitutive SUR2A/Kir6.1 opening leads to systemic vasorelaxation and hypotension, leading to compensatory cardiac hypertrophy and hypercontractility and PH ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension

Ribeuz

Masson

Dutheil

et al. 2023

Front. Cardiovasc. Med.

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AimsWe hypothesized that the ATP-sensitive K+ channels (KATP) regulatory subunit (ABCC9) contributes to PAH pathogenesis. ABCC9 gene encodes for two regulatory subunits of KATP channels: the SUR2A and SUR2B proteins. In the KATP channel, the SUR2 subunits are associated with the K+ channel Kir6.1. We investigated how the SUR2/Kir6.1 channel contributes to PAH pathogenesis and its potential as a therapeutic target in PAH.Methods and resultsUsing in vitro, ex vivo, and in vivo approaches, we analyzed the localization and expression of SUR2A, SUR2B, and Kir6.1 in the pulmonary vasculature of controls and patients with PAH as in experimental pulmonary hypertension (PH) rat models and its contribution to PAH physiopathology. Finally, we deciphered the consequences of in vivo activation of SUR2/Kir6.1 in the monocrotaline (MCT)-induced PH model. We found that SUR2A, SUR2B, and Kir6.1 were expressed in the lungs of controls and patients with PAH and MCT-induced PH rat models. Organ bath studies showed that SUR2 activation by pinacidil induced relaxation of pulmonary arterial in rats and humans. In vitro experiments on human pulmonary arterial smooth muscle cells and endothelial cells (hPASMCs and hPAECs) in controls and PAH patients showed decreased cell proliferation and migration after SUR2 activation. We demonstrated that SUR2 activation in rat right ventricular (RV) cardiomyocytes reduced RV action potential duration by patch-clamp. Chronic pinacidil administration in control rats increased heart rate without changes in hemodynamic parameters. Finally, in vivo pharmacological activation of SUR2 on MCT and Chronic-hypoxia (CH)-induced-PH rats showed improved PH.ConclusionWe showed that SUR2A, SUR2B, and Kir6.1 are presented in hPASMCs and hPAECs of controls and PAH patients. In vivo SUR2 activation reduced the MCT-induced and CH-induced PH phenotype, suggesting that SUR2 activation should be considered for treating PAH.

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Section: Discussionmentioning

confidence: 99%

Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension

Ribeuz

Masson

Dutheil

et al. 2023

Front. Cardiovasc. Med.

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“…Cantú syndrome (CS) is an ultrarare autosomal dominant inherited disorder caused by dominant gain-of-function mutations in both the SUR2A and Kir6.1 subunits of the K ATP channel, which is also characterized by multiple cardiovascular abnormalities, including edema, pericardial effusion, pulmonary hypertension, dilated and tortuous blood vessels with decreased systemic vascular resistance, cerebrovascular defects, patent ductus arteriosus, and marked cardiac hypertrophy ( Chen et al, 2019 ; Chihara et al, 2020 ; McClenaghan et al, 2020 ; Zhang et al, 2021a ) ( Table 3 ). CHI is a rare genetically heterogeneous disorder caused by inactivating mutations in the SUR1 and Kir6.2 subunits of the K ATP channel and it is characterized by persistent hypoglycemia in infants and children, which may increase the risk of permanent brain damage ( Boodhansingh et al, 2019 ; Rosenfeld et al, 2019 ; Männistö et al, 2020 ; Rosenfeld et al, 2021 ).…”

Section: Mutation Of K Atp Channelsmentioning

confidence: 99%

Functional Regulation of KATP Channels and Mutant Insight Into Clinical Therapeutic Strategies in Cardiovascular Diseases

et al. 2022

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ATP-sensitive potassium channels (KATP channels) play pivotal roles in excitable cells and link cellular metabolism with membrane excitability. The action potential converts electricity into dynamics by ion channel-mediated ion exchange to generate systole, involved in every heartbeat. Activation of the KATP channel repolarizes the membrane potential and decreases early afterdepolarization (EAD)-mediated arrhythmias. KATP channels in cardiomyocytes have less function under physiological conditions but they open during severe and prolonged anoxia due to a reduced ATP/ADP ratio, lessening cellular excitability and thus preventing action potential generation and cell contraction. Small active molecules activate and enhance the opening of the KATP channel, which induces the repolarization of the membrane and decreases the occurrence of malignant arrhythmia. Accumulated evidence indicates that mutation of KATP channels deteriorates the regulatory roles in mutation-related diseases. However, patients with mutations in KATP channels still have no efficient treatment. Hence, in this study, we describe the role of KATP channels and subunits in angiocardiopathy, summarize the mutations of the KATP channels and the functional regulation of small active molecules in KATP channels, elucidate the potential mechanisms of mutant KATP channels and provide insight into clinical therapeutic strategies.

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“…Sulfonylureas and glinides are insulin secretion stimulating drugs that work via inhibition of ATP‐sensitive K + (K ATP ) channel. The K ATP channel is an octameric complex composing of inwardly rectifying K + channels (Kir6.1 and Kir6.2) and sulfonylurea receptor subunits (SUR1, SUR2A, and SUR2B) in a tissue‐dependent manner 29 . In skeletal muscle, the Kir6.2/SUR2A subunits constitute the main K ATP channel complex, while other SUR subunits are expressed in different types of muscle 30 .…”

Section: Effects Of Anti‐diabetic Drugs On the Musclementioning

confidence: 99%

“…The K ATP channel is an octameric complex composing of inwardly rectifying K + channels (Kir6.1 and Kir6.2) and sulfonylurea receptor subunits (SUR1, SUR2A, and SUR2B) in a tissue‐dependent manner. 29 In skeletal muscle, the Kir6.2/SUR2A subunits constitute the main K ATP channel complex, while other SUR subunits are expressed in different types of muscle. 30 Preclinical data have linked K ATP channel blockers to muscle atrophy.…”

Section: Effects Of Anti‐diabetic Drugs On the Musclementioning

confidence: 99%

Anti‐diabetic drugs and sarcopenia: emerging links, mechanistic insights, and clinical implications

Zhang

Zhao

Chen

et al. 2021

J cachexia sarcopenia muscle

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Sarcopenia, characterized by loss of skeletal muscle mass, quality, and strength, has become a common hallmark of ageing and many chronic diseases. Diabetes mellitus patients have a higher prevalence of sarcopenia, which greatly aggravates the metabolic disturbance and compromises treatment response. Preclinical and clinical studies have shown differential impacts of anti‐diabetic drugs on skeletal muscle mass, strength, and performance, highlighting the importance of rational therapeutic regimen from the perspective of sarcopenia risk. In this review, we provide an update on the regulation of muscle mass and quality by major anti‐diabetic drugs, focusing primarily on emerging data from clinical studies. We also discuss the underlying mechanisms and clinical implications for optimal selection of anti‐diabetic drugs to reduce the risk of sarcopenia. In view of the lifelong use of anti‐diabetic drugs, we propose that a better understanding of the sarcopenia risk and interventional strategies is worthy of attention in future studies.

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Complex consequences of Cantu syndrome SUR2 variant R1154Q in genetically modified mice

Cited by 11 publications

References 51 publications

Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension

Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension

Functional Regulation of KATP Channels and Mutant Insight Into Clinical Therapeutic Strategies in Cardiovascular Diseases

Anti‐diabetic drugs and sarcopenia: emerging links, mechanistic insights, and clinical implications

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