Isolation of Mouse Interstitial Valve Cells to Study the Calcification of the Aortic Valve <em>In Vitro</em>

The calcification of aortic valve cells is the hallmark of aortic stenosis and is associated with valve cusp fibrosis. Valve interstitial cells (VICs) ...

The Icahn School of Medicine at Mount Sinai

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According to the International Diabetes Federation the number of people between the ages of 20 and 79 years diagnosed with diabetes mellitus is projected to reach 380 million worldwide by 2025. Cardiovascular disease, including heart failure, is the major cause of death in patients with diabetes. A contributing factor to heart failure in such patients is the development of diabetic cardiomyopathy--a clinical myocardial condition distinguished by ventricular dysfunction that can present independently of other risk factors such as hypertension or coronary artery disease. This disorder has been associated with both type 1 and type 2 diabetes, and is characterized by early-onset diastolic dysfunction and late-onset systolic dysfunction. The development of diabetic cardiomyopathy and the cellular and molecular perturbations associated with the pathology are complex and multifactorial. Hallmark mechanisms include abnormalities in regulation of calcium homeostasis, and associated abnormal ventricular excitation-contraction coupling, metabolic disturbances, and alterations in insulin signaling. An emerging concept is that disruptions in calcium homeostasis might be linked to diminished insulin responsiveness. An understanding of the cellular effect of these abnormalities on cardiomyocytes should be useful in predicting the maladaptive cardiac structural and functional consequences of diabetes.

Interplay between impaired calcium regulation and insulin signaling abnormalities in diabetic cardiomyopathy.

Selon la F&#xE9;d&#xE9;ration Internationale du Diab&#xE8;te le nombre de personnes entre les &#xE2;ges de 20 et 79 ans diagnostiqu&#xE9;s avec le diab&#xE8;te sucr&#xE9; devrait atteindre 380 millions dans le monde d&#x26;#39;ici 2025. Les maladies cardiovasculaires, notamment l&#x26;#39;insuffisance cardiaque, est la principale cause de d&#xE9;c&#xE8;s chez les patients atteints de diab&#xE8;te. Un facteur qui contribue &#xE0; l&#x26;#39;insuffisance cardiaque chez ces patients est le d&#xE9;veloppement de la cardiomyopathie diab&#xE9;tique - un &#xE9;tat clinique du myocarde se distingue par une dysfonction ventriculaire qui peuvent pr&#xE9;senter ind&#xE9;pendamment des facteurs de risque tels que l&#x26;#39;hypertension ou une maladie coronarienne. Ce trouble a &#xE9;t&#xE9; associ&#xE9; &#xE0; la fois de type 1 et diab&#xE8;te de type 2, et se caract&#xE9;rise par l&#x26;#39;apparition pr&#xE9;coce dysfonction diastolique et une dysfonction systolique tardive. Le d&#xE9;veloppement de la cardiomyopathie diab&#xE9;tique et les perturbations cellulaires et mol&#xE9;culaires associ&#xE9;s &#xE0; la pathologie sont complexes et multifactorielles. M&#xE9;canismes Hallmark comprennent des anomalies dans la r&#xE9;gulation de l&#x26;#39;hom&#xE9;ostasie calcique et associ&#xE9; ventriculaire anormale couplage excitation-contraction, des troubles m&#xE9;taboliques et des modifications dans la signalisation insulinique. Un nouveau concept est que les perturbations dans l&#x26;#39;hom&#xE9;ostasie du calcium pourrait &#xEA;tre li&#xE9;e &#xE0; une diminution r&#xE9;ponse &#xE0; l&#x26;#39;insuline. Une bonne compr&#xE9;hension de l&#x26;#39;effet cellulaire de ces anomalies sur des cardiomyocytes devrait &#xEA;tre utile pour pr&#xE9;dire les cons&#xE9;quences cardiaques m&#xE9;sadapt&#xE9;s structurelles et fonctionnelles du diab&#xE8;te.

Interaction entre la r&#xE9;gulation du calcium avec facult&#xE9;s affaiblies et anomalies signalisation de l&#x26;#39;insuline dans la cardiomyopathie diab&#xE9;tique

Laut der International Diabetes Federation ist die Zahl der Menschen im Alter von 20 und 79 Jahren mit Diabetes Mellitus diagnostiziert Projektionen um 380 Millionen weltweit zu erreichen bis zum Jahr 2025. Herz-Kreislauf-Erkrankungen, einschlie&szlig;lich Herzinsuffizienz, ist die Hauptursache des Todes bei Patienten mit Diabetes. Ein beitragender Faktor zum Herzversagen bei solchen Patienten ist die Entwicklung der Diabetische Kardiomyopathie--eine klinische myokardialen Bedingung durch ventrikul&auml;re Dysfunktion, die unabh&auml;ngig von anderen Risikofaktoren wie Bluthochdruck oder koronare Krankheit darstellen kann. Diese St&ouml;rung wurde verkn&uuml;pft mit Typ 1 und Typ 2 Diabetes und ist gekennzeichnet durch fr&uuml;h einsetzende diastolische Dysfunktion und sp&auml;t beginnende systolische Dysfunktion. Die Entwicklung der Diabetische Kardiomyopathie und die Perturbationen zellul&auml;ren und molekularen Pathologie zugeordnet sind komplex und multifaktoriell. Markenzeichen Mechanismen geh&ouml;ren Anomalien in Regulation des Kalzium-Hom&ouml;ostase und zugeh&ouml;rigen abnorme ventrikul&auml;re Erregung-Kontraktion Koppelung, metabolische St&ouml;rungen und Ver&auml;nderungen in Insulin zu signalisieren. Eine aufstrebende Konzept ist, dass St&ouml;rungen im Kalzium-Hom&ouml;ostase verkn&uuml;pft werden k&ouml;nnte, um Insulin Reaktionsf&auml;higkeit vermindert. Ein Verst&auml;ndnis f&uuml;r die zellul&auml;re Wirkung von diese Anomalien auf Cardiomyocytes sollte bei der Vorhersage der abgebaut kardialen strukturellen und funktionellen Folgen von Diabetes n&uuml;tzlich sein.

Interplay zwischen gest&ouml;rter Kalzium Regulierung und Insulin Signalisierung Anomalien im Diabetische Kardiomyopathie.

Secondo la Federazione internazionale diabete il numero di persone di et&agrave; compresa tra i 20 e i 79 anni diagnosticati con il diabete mellito &egrave; proiettato per raggiungere 380 milioni in tutto il mondo entro il 2025. Le malattie cardiovascolari, tra cui insufficienza cardiaca, sono la principale causa di morte nei pazienti con diabete. Un fattore che contribuisce all&#39;insufficienza cardiaca in tali pazienti &egrave; lo sviluppo di cardiomiopatia diabetica, una condizione clinica del miocardio caratterizzata da disfunzione ventricolare che pu&ograve; presentare indipendentemente da altri fattori di rischio come l&#39;ipertensione o malattia coronarica. Questo disturbo &egrave; stato associato sia di tipo 1 e diabete di tipo 2 ed &egrave; caratterizzato da esordio precoce disfunzione diastolica e disfunzione sistolica ad esordio tardivo. Lo sviluppo di cardiomiopatia diabetica e le perturbazioni cellulari e molecolari connessi con la patologia sono complesse e multifattoriali. Hallmark meccanismi includono anomalie nella regolazione del calcio l&#39;omeostasi e accoppiamento eccitazione-contrazione ventricolare anomala associata, metaboliche disturbi e alterazioni nella segnalazione di insulina. Un concetto emergente &egrave; che interruzioni nell&#39;omeostasi del calcio potrebbero essere legati alla diminuita Reattivit&agrave; insulina. La comprensione dell&#39;effetto di queste anomalie cellulare su cardiomyocytes dovrebbe essere utile nel predire il disadattamento cardiache strutturale e funzionale conseguenze del diabete.

Interplay tra calcio alterata regolazione e segnalazione anomalie nella cardiomiopatia diabetica insulina.

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Seg&#xFA;n la Federaci&#xF3;n Internacional de Diabetes en el n&#xFA;mero de personas entre las edades de 20 y 79 a&#xF1;os con diagn&#xF3;stico de diabetes mellitus se prev&#xE9; que alcanzar&#xE1; los 380 millones en todo el mundo para el a&#xF1;o 2025. Las enfermedades cardiovasculares, incluyendo insuficiencia cardiaca, es la principal causa de muerte en pacientes con diabetes. Un factor que contribuye a la insuficiencia cardiaca en estos pacientes es el desarrollo de la cardiomiopat&#xED;a diab&#xE9;tica - una condici&#xF3;n cl&#xED;nica del miocardio caracteriza por la disfunci&#xF3;n ventricular que puede presentar independientemente de otros factores de riesgo como la hipertensi&#xF3;n o enfermedad coronaria. Este trastorno se ha asociado con el tipo 1 y diabetes tipo 2, y se caracteriza por la aparici&#xF3;n temprana disfunci&#xF3;n diast&#xF3;lica y de inicio tard&#xED;o disfunci&#xF3;n sist&#xF3;lica. El desarrollo de la miocardiopat&#xED;a diab&#xE9;tica y las perturbaciones celulares y moleculares asociados con la patolog&#xED;a es compleja y multifactorial. Mecanismos de Hallmark incluyen anormalidades en la regulaci&#xF3;n de la homeostasis del calcio, y asociado de acoplamiento anormal de excitaci&#xF3;n-contracci&#xF3;n ventricular, trastornos metab&#xF3;licos y alteraciones en la se&#xF1;alizaci&#xF3;n de la insulina. Un nuevo concepto es que las perturbaciones en la homeostasis del calcio podr&#xED;a estar relacionada con la disminuci&#xF3;n de respuesta a la insulina. La comprensi&#xF3;n de los efectos celulares de estas anomal&#xED;as en los cardiomiocitos debe ser &#xFA;til para predecir las consecuencias desadaptativas card&#xED;acas estructurales y funcionales de la diabetes.

Interacci&#xF3;n entre la regulaci&#xF3;n del calcio alterada y Anomal&#xED;as se&#xF1;alizaci&#xF3;n de insulina en la miocardiopat&#xED;a diab&#xE9;tica

Pathological left ventricle (LV) hypertrophy (LVH) results in reactive and replacement fibrosis. Volume overload LVH (VOH) is less profibrotic than pressure overload LVH (POH). Studies attribute subendocardial fibrosis in POH to ischaemia, and reduced fibrosis in VOH to collagen degradation favouring dilatation. However, the mechanical origin of the relative lack of fibrosis in VOH is incompletely understood. We hypothesized that reduced ischaemia propensity in VOH compared to POH accounted for the reduced replacement fibrosis, along with reduced reactive fibrosis. Rats with POH (ascending aortic banding) evolved into either compensated-concentric POH (POH-CLVH) or dilated cardiomyopathy (POH-DCM); they were compared to VOH (aorta-caval fistula). We quantified LV fibrosis, structural and haemodynamic factors of ischaemia propensity, and the activation of profibrotic pathways. Fibrosis in POH-DCM was severe, subendocardial and subepicardial, in contrast with subendocardial fibrosis in POH-CLVH and nearly no fibrosis in VOH. The propensity for ischaemia was more important in POH versus VOH, explaining different patterns of replacement fibrosis. LV collagen synthesis and maturation, and matrix metalloproteinase-2 expression, were more important in POH. The angiotensin II-transforming growth-factor β axis was enhanced in POH, and connective tissue growth factor (CTGF) was overexpressed in all types of LVH. LV resistin expression was markedly elevated in POH, mildly elevated in VOH and independently reflected chronic ischaemic injury after myocardial infarction. In vitro, resistin is induced by angiotensin II and induces CTGF in cardiomyocytes. Based on these findings, we conclude that a reduced ischaemia propensity and attenuated upstream reactive fibrotic pathways account for the attenuated fibrosis in VOH versus POH.

Differential patterns of replacement and reactive fibrosis in pressure and volume overload are related to the propensity for ischaemia and involve resistin.

Dysregulation of endoplasmic reticulum (ER) Ca(2+) homeostasis triggers ER stress leading to the development of insulin resistance in obesity and diabetes. Impaired function of the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) has emerged as a major contributor to ER stress. We pharmacologically activated SERCA2b in a genetic model of insulin resistance and type 2 diabetes (ob/ob mice) with a novel allosteric activator, CDN1163, which markedly lowered fasting blood glucose, improved glucose tolerance, and ameliorated hepatosteatosis but did not alter glucose levels or body weight in lean controls. Importantly, CDN1163-treated ob/ob mice maintained euglycemia comparable with that of lean mice for >6 weeks after cessation of CDN1163 administration. CDN1163-treated ob/ob mice showed a significant reduction in adipose tissue weight with no change in lean mass, assessed by magnetic resonance imaging. They also showed an increase in energy expenditure using indirect calorimetry, which was accompanied by increased expression of uncoupling protein 1 (UCP1) and UCP3 in brown adipose tissue. CDN1163 treatment significantly reduced the hepatic expression of genes involved in gluconeogenesis and lipogenesis, attenuated ER stress response and ER stress-induced apoptosis, and improved mitochondrial biogenesis, possibly through SERCA2-mediated activation of AMP-activated protein kinase pathway. The findings suggest that SERCA2b activation may hold promise as an effective therapy for type-2 diabetes and metabolic dysfunction. 

Small Molecular Allosteric Activator of the Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA) Attenuates Diabetes and Metabolic Disorders.

Cardiovascular (CV) diseases in type 2 diabetes (T2DM) represent an enormous burden with high mortality and morbidity. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently emerged as a new antidiabetic class that improves glucose control, as well as body weight and blood pressure with no increased risk of hypoglycemia. The first CV outcome study terminated with empagliflozin, a specific SGLT2 inhibitor, has shown a reduction in CV mortality and in heart failure hospitalization, suggesting a beneficial impact on cardiac function which remains to be demonstrated. This study was designed to examine the chronic effect of empagliflozin on left ventricular (LV) systolic and diastolic functions in a genetic model of T2DM, ob/ob mice.

Empagliflozin Improves Left Ventricular Diastolic Dysfunction in a Genetic Model of Type 2 Diabetes.

Intracellular calcium (Ca is a critical coordinator of various aspects of cellular physiology. It is increasingly apparent that changes in cellular Ca dynamics contribute to the regulation of normal and pathological signal transduction that controls cell growth and survival. Aberrant perturbations in Ca homeostasis have been implicated in a range of pathological conditions, such as cardiovascular diseases, diabetes, tumorigenesis and steatosis hepatitis. Intracellular Ca concentrations are therefore tightly regulated by a number of Ca handling enzymes, proteins, channels and transporters located in the plasma membrane and in Ca storage organelles, which work in concert to fine tune a temporally and spatially precise Ca signal. Chief amongst them is the sarco/endoplasmic reticulum (SR/ER) Ca ATPase pump (SERCA) which actively re-accumulates released Ca back into the SR/ER, therefore maintaining Ca homeostasis. There are at least 14 different SERCA isoforms encoded by three ATP2A1-3 genes whose expressions are species- and tissue-specific. Altered SERCA expression and activity results in cellular malignancy and induction of ER stress and ER stress-associated apoptosis. The role of SERCA misregulation in the control of apoptosis in various cell types and disease setting with prospective therapeutic implications is the focus of this review. Ca is a double edge sword for both life as well as death, and current experimental evidence supports a model in which Ca homeostasis and SERCA activity represent a nodal point that controls cell survival. Pharmacological or genetic targeting of this axis constitutes an incredible therapeutic potential to treat different diseases sharing similar biological disorders.

SERCA control of cell death and survival.

The adipokine resistin has been proposed to link obesity, insulin resistance and diabetes. We have previously reported that diabetic hearts express high levels of resistin while overexpression of resistin in adult rat hearts gives rise to a phenotype resembling diabetic cardiomyopathy. The transcriptional regulation of resistin in diabetic cardiac tissue is currently unknown. This study investigated the mechanism of resistin upregulation and the role of Serca2a in its transcriptional suppression. We demonstrate that restoration of Ca homeostasis in diabetic hearts, through normalization of Serca2a function genetically and pharmacologically, suppressed resistin expression via inhibition of NFATc. H9c2 myocytes stimulated with high-glucose concentration or Ca time-dependently increased NFATc and resistin expression while addition of the Ca chelator BAPTA-AM attenuated this effect. NFATc expression was enhanced in hearts from ob/ob diabetic and from cardiac-specific Serca2a mice. Similarly, NFATc increased resistin expression in myocytes cultured in low glucose while the NFATc inhibitor VIVIT blocked glucose-induced resistin expression, suggesting that hyperglycemia/diabetes induces resistin expression possibly through NFATc activation. Interestingly, overexpression of Serca2a or VIVIT mitigated glucose-stimulated resistin and NFATc expression and enhanced AMPK activity, a downstream target of resistin signaling. NFATc direct activation of resistin was verified by resistin promoter luciferase activity and chromatin-immunoprecipitation analysis. Interestingly, activation of Serca2a by a novel agonist, CDN1163, mirrored the effects of AAV9-Serca2a gene transfer on resistin expression and its promoter activity and AMPK signaling in diabetic mice. These findings parse a role for Ca in resistin transactivation and provide support that manipulation of Serca2a-NFATc-Resistin axis might be useful in hyper-resistinemic conditions.

A role for calcium in resistin transcriptional activation in diabetic hearts.

Myocardial fibrosis is a major determinant of clinical outcomes in heart failure (HF) patients. It is characterized by the emergence of myofibroblasts and early activation of pro-fibrotic signaling pathways before adverse ventricular remodeling and progression of HF. Boron has been reported in recent years to augment the innate immune system and cell proliferation, which play an important role in the repair and regeneration of the injured tissue. Currently, the effect of boron on cardiac contractility and remodeling is unknown. In this study, we investigated, for the first time, the effect of boron supplementation on cardiac function, myocardial fibrosis, apoptosis and regeneration in a rat model myocardial infarction (MI)-induced HF. MI was induced in animals and borax, a sodium salt of boron, was administered for 7 days, p.o., 21 days post-injury at a dose level of 4 mg/kg body weight. Transthoracic echocardiographic analysis showed a significant improvement in systolic and diastolic functions with boron treatment compared to saline control. In addition, boron administration showed a marked reduction in myocardial fibrosis and apoptosis in the injured hearts, highlighting a protective effect of boron in the ischemic heart. Interestingly, we observed a tenfold increase of nuclei in thin myocardial sections stained positive for the cell cycle marker Ki67 in the MI boron-treated rats compared to saline, indicative of increased cardiomyocyte cell cycle activity in MI hearts, highlighting its potential role in regeneration post-injury. We similarly observed increased Ki67 and BrdU staining in cultured fresh neonatal rat ventricular cardiomyocytes. Collectively, the results show that boron positively impacted MI-induced HF and attenuated cardiac fibrosis and apoptosis, two prominent features of HF. Importantly, boron has the potential to induce cardiomyocyte cell cycle entry and potentially cardiac tissue regeneration after injury. Boron might be beneficial as a supplement in MI and may be a good candidate substance for anti-fibrosis approach.

Boron improves cardiac contractility and fibrotic remodeling following myocardial infarction injury.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic heart muscle disease characterized by hypertrophy with preserved or increased ejection fraction in the absence of secondary causes. However, recent studies have demonstrated that a substantial proportion of individuals with HCM also have comorbid diabetes mellitus (~10%). Whether genetic variants may contribute a combined phenotype of HCM and diabetes mellitus is not known. Here, using next-generation sequencing methods, we identified novel and ultrarare variants in adiponectin receptor 1 () as risk factors for HCM. Biochemical studies showed that  variants dysregulate glucose and lipid metabolism and cause cardiac hypertrophy through the p38/mammalian target of rapamycin and/or extracellular signal-regulated kinase pathways. A transgenic mouse model expressing an  variant displayed cardiomyopathy that recapitulated the cellular findings, and these features were rescued by rapamycin. Our results provide the first evidence that  variants can cause HCM and provide new insights into  regulation.

Adiponectin receptor 1 variants contribute to hypertrophic cardiomyopathy that can be reversed by rapamycin.

Cardiac fibrosis is characterized by excessive deposition of extracellular matrix proteins and myofibroblast differentiation. Our previous findings have implicated resistin in cardiac fibrosis; however, the molecular mechanisms underlying this process are still unclear. Here we investigated the role of resistin in fibroblast-to-myofibroblast differentiation and elucidated the pathways involved in this process. Fibroblast-to-myofibroblast transdifferentiation was induced with resistin or TGFβ1 in NIH-3T3 and adult cardiac fibroblasts. mRNA and protein expression of fibrotic markers were analyzed by qPCR and immunoblotting. Resistin-knockout mice, challenged with a high-fat diet (HFD) for 20 weeks to stimulate cardiac impairment, were analyzed for cardiac function and fibrosis using histologic and molecular methods. Cardiac fibroblasts stimulated with resistin displayed increased fibroblast-to-myofibroblast conversion, with increased levels of αSma, col1a1, Fn, Ccn2 and Mmp9, with remarkable differences in the actin network appearance. Mechanistically, resistin promotes fibroblast-to-myofibroblast transdifferentiation and fibrogenesis via JAK2/STAT3 and JNK/c-Jun signaling pathways, independent of TGFβ1. Resistin-null mice challenged with HFD showed an improvement in cardiac function and a decrease in tissue fibrosis and reduced mRNA levels of fibrogenic markers. These findings are the first to delineate the role of resistin in the process of cardiac fibroblast-to-myofibroblast differentiation via JAK/STAT3 and JNK/c-Jun pathways, potentially leading to stimulation of cardiac fibrosis.

Resistin induces cardiac fibroblast-myofibroblast differentiation through JAK/STAT3 and JNK/c-Jun signaling.

This study analyzed the expression of extracellular matrix (ECM) proteins during aortic valve calcification with mass spectrometry, and further validated in an independent human cohort using RNAseq data. The study reveals that valve calcification is associated with significant disruption in ECM and metabolic pathways, and highlights a strong connection between metabolic markers and ECM remodeling. It also identifies FNDC1 and MXRA5 as novel ECM biomarkers in calcified valves, electing them as potential targets in the development and progression of aortic stenosis.

Djamel Lebeche

Cardiovascular Research Center,
Diabetes,
Obesity and Metabolism Institute,
Department of Medicine,
Graduate School of Biomedical Sciences,
Diabetes, Obesity and Metabolism Institute, Department of Medicine

The Icahn School of Medicine at Mount Sinai

Isolation of Mouse Interstitial Valve Cells to Study the Calcification of the Aortic Valve In Vitro

Djamel Lebeche

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Cardiovascular Research Center,Diabetes,Obesity and Metabolism Institute,Department of Medicine,Graduate School of Biomedical Sciences,Diabetes, Obesity and Metabolism Institute, Department of Medicine

The Icahn School of Medicine at Mount Sinai

Isolation of Mouse Interstitial Valve Cells to Study the Calcification of the Aortic Valve In Vitro

Cardiovascular Research Center,
Diabetes,
Obesity and Metabolism Institute,
Department of Medicine,
Graduate School of Biomedical Sciences,
Diabetes, Obesity and Metabolism Institute, Department of Medicine