F ailure of the coronary circulation to meet the constant demands of the cardiomyocytes results in ischemic heart disease or infarction. Determining the factors that regulate coronary blood flow is, therefore, crucial for understanding pathophysiological manifestations and for the development of new therapeutic strategies. Voltage-gated potassium channels (K V ) have been implicated in the control of the coronary circulation and reactive hyperemia, 1,2 but little is known about the specific molecular components. Kv channels encoded by KCNQ1-5 (K V 7.1-K V 7.5) are important regulators of the smooth muscle resting membrane potential and contractility in several different rodent and human arteries, [3][4][5][6][7][8][9][10][11] which are known to be compromised in animal models of primary and secondary hypertension. 3,6 These channels, in particular K V 7.4, are also functional end points in β-adrenoceptor-mediated relaxations.3 These combined observations provide a mechanism by which arteries become relatively resistant to endogenous vasorelaxants. However, little is known about K V 7 expression levels or the functional importance of these channels in coronary arteries.Consequently, we determined the expression profiles of KCNQ genes and the functional impact of K V 7 channel modulators in left anterior descending (LAD) coronary arteries. We also ascertained whether K V 7 channels contribute to relaxations produced by adenosine, which is released rapidly after myocardial ischemia in vivo and acts as a local metabolic regulator of coronary flow. 12,13 This study demonstrates that K V 7 channels are key regulators of coronary flow at rest, and they also contribute to adenosine-mediated dilatations and the active response to ischemia. MethodsFor more complete descriptions, see the online-only Data Supplement. AnimalsThe study complies with the European Community Guidelines for the Care and Use of Experimental Animals and was approved by the Animal Ethics Screening Committee in Denmark (license number: 2010/561-1799) and by the UK Animal (Scientific Procedures) Act 1986. Male, normotensive Wistar Hannover rats and spontaneously hypertensive rats (SHRs), aged 11 to 16 weeks, were purchased from Abstract-The goal of the present study was to determine the role of KCNQ-encoded K V channels (K V 7 channels) in the passive and active regulation of coronary flow in normotensive and hypertensive rats. In left anterior descending coronary arteries from normotensive rats, structurally different K V 7.2 to 7.5 activators produced relaxations, which were considerably less in arteries from hypertensive rats and were not mimicked by the K V 7.1-specific activator R-L3. In isolated, perfused heart preparations, coronary flow rate increased in response to the K V 7.2 to 7.5 activator (S)-1 and was diminished in the presence of a K V 7 inhibitor. The expression levels of KCNQ1-5 and their known accessory KCNE1-5 subunits in coronary arteries were similar in normotensive and hypertensive rats as measured by quantitative polymerase cha...
Mutations in LMNA, the gene that encodes lamin A and C, causes LMNA-related dilated cardiomyopathy (DCM) or cardiolaminopathy. LMNA is expressed in endothelial cells (ECs); however, little is known about the EC-specific phenotype of LMNA-related DCM. Here, we studied a family affected by DCM due to a frameshift variant in LMNA. Human induced pluripotent stem cell (iPSC)–derived ECs were generated from patients with LMNA-related DCM and phenotypically characterized. Patients with LMNA-related DCM exhibited clinical endothelial dysfunction, and their iPSC-ECs showed decreased functionality as seen by impaired angiogenesis and nitric oxide (NO) production. Moreover, genome-edited isogenic iPSC lines recapitulated the EC disease phenotype in which LMNA-corrected iPSC-ECs showed restoration of EC function. Simultaneous profiling of chromatin accessibility and gene expression dynamics by combining assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing (RNA-seq) as well as loss-of-function studies identified Krüppel-like factor 2 (KLF2) as a potential transcription factor responsible for the EC dysfunction. Gain-of-function studies showed that treatment of LMNA iPSC-ECs with KLF2 agonists, including lovastatin, rescued the EC dysfunction. Patients with LMNA-related DCM treated with lovastatin showed improvements in clinical endothelial dysfunction as indicated by increased reactive hyperemia index. Furthermore, iPSC-derived cardiomyocytes (iPSC-CMs) from patients exhibiting the DCM phenotype showed improvement in CM function when cocultured with iPSC-ECs and lovastatin. These results suggest that impaired cross-talk between ECs and CMs can contribute to the pathogenesis of LMNA-related DCM, and statin may be an effective therapy for vascular dysfunction in patients with cardiolaminopathy.
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