assessment-right-ventricular-structure-function-mouse-model-pulmonary

Assessment of Right Ventricular Structure and Function in Mouse Model of Pulmonary Artery Constriction by Transthoracic Echocardiography

Emerging clinical data support the notion that RV dysfunction is critical to the pathogenesis of cardiovascular disease and heart failure1-3. Moreover, ...

early-detection-drug-induced-renal-hemodynamic-dysfunction-using

Early Detection of Drug-Induced Renal Hemodynamic Dysfunction Using Sonographic Technology in Rats

The kidney normally functions to maintain hemodynamic homeostasis and is a major site of damage caused by drug toxicity. Drug-induced nephrotoxicity is ...

ultrasound-based-assessment-coronary-artery-flow-coronary-flow

Ultrasound Based Assessment of Coronary Artery Flow and Coronary Flow Reserve Using the Pressure Overload Model in Mice

Transthoracic Doppler echocardiography (TTDE) is a clinically useful, noninvasive tool for studying coronary artery flow velocity and coronary flow ...

high-frequency-ultrasound-echocardiography-to-assess-zebrafish

High-Frequency Ultrasound Echocardiography to Assess Zebrafish Cardiac Function

The zebrafish (Danio rerio) has become a very popular model organism in cardiovascular research, including human cardiac diseases, largely due to its ...

Harvard Medical School

Brigham and Women's Hospital, Harvard Medical School

In the postabsorptive state, certain tissues, including the brain, require glucose as the sole source of energy. After an overnight fast, hepatic glycogen stores are depleted, and gluconeogenesis becomes essential for preventing life-threatening hypoglycemia. Mice with a targeted deletion of KLF15, a member of the Krüppel-like family of transcription factors, display severe hypoglycemia after an overnight (18 hr) fast. We provide evidence that defective amino acid catabolism promotes the development of fasting hypoglycemia in KLF15-/- mice by limiting gluconeogenic substrate availability. KLF15-/- liver and skeletal muscle show markedly reduced mRNA expression of amino acid-degrading enzymes. Furthermore, the enzymatic activity of alanine aminotransferase (ALT), which converts the critical gluconeogenic amino acid alanine into pyruvate, is decreased (approximately 50%) in KLF15-/- hepatocytes. Consistent with this observation, intraperitoneal injection of pyruvate, but not alanine, rescues fasting hypoglycemia in KLF15-/- mice. We conclude that KLF15 plays an important role in the regulation of gluconeogenesis.

Regulation of gluconeogenesis by Krüppel-like factor 15.

The Krüppel-like family of transcription factors play diverse roles regulating cellular differentiation and tissue development. Accumulating evidence supports an important role for these factors in vascular biology. This review examines the current knowledge of this gene family's role in key cell types that critically regulate vessel biology under physiologic and pathologic states.

An emerging role for Krüppel-like factors in vascular biology.

Cardiac hypertrophy is a common response to injury and hemodynamic stress and an important harbinger of heart failure and death. Herein, we identify the Kruppel-like factor 15 (KLF15) as an inhibitor of cardiac hypertrophy. Myocardial expression of KLF15 is reduced in rodent models of hypertrophy and in biopsy samples from patients with pressure-overload induced by chronic valvular aortic stenosis. Overexpression of KLF15 in neonatal rat ventricular cardiomyocytes inhibits cell size, protein synthesis and hypertrophic gene expression. KLF15-null mice are viable but, in response to pressure overload, develop an eccentric form of cardiac hypertrophy characterized by increased heart weight, exaggerated expression of hypertrophic genes, left ventricular cavity dilatation with increased myocyte size, and reduced left ventricular systolic function. Mechanistically, a combination of promoter analyses and gel-shift studies suggest that KLF15 can inhibit GATA4 and myocyte enhancer factor 2 function. These studies identify KLF15 as part of a heretofore unrecognized pathway regulating the cardiac response to hemodynamic stress.

Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy.

&#x5FC3;&#x808C;&#x7EA4;&#x7EF4;&#x5316;&#x662F;&#x5FC3;&#x810F;&#x7684;&#x8840;&#x6D41;&#x52A8;&#x529B;&#x5B66;&#x6216;&#x4F53;&#x6DB2;&#x7684;&#x5E94;&#x6FC0;&#x53CD;&#x5E94;&#x7684;&#x75C5;&#x7406;&#x91CD;&#x5851;&#x6807;&#x5FD7;&#x529F;&#x80FD;&#x3002;&#x8D8A;&#x6765;&#x8D8A;&#x591A;&#x7684;&#x8BC1;&#x636E;&#x6D89;&#x53CA;&#x7ED3;&#x7F14;&#x7EC4;&#x7EC7;&#x751F;&#x957F;&#x56E0;&#x5B50; &#xFF08;CTGF&#xFF09; &#x4F5C;&#x4E3A;&#x8FD9;&#x4E00;&#x8FDB;&#x7A0B;&#x7684;&#x4E3B;&#x8981;&#x8C03;&#x89E3;&#x4EBA;&#x3002;&#x6211;&#x4EEC;&#x7EC4;&#x4EE5;&#x524D;&#x5DF2;&#x5217;&#x4E3A;&#x91CD;&#x8981;&#x76D1;&#x7BA1;&#x673A;&#x6784;&#x7684;&#x538B;&#x529B; &#xFF1B; &#x5FC3;&#x810F;&#x91CD;&#x6784;&#x56E0;&#x5B50; 15 Kruppel-Like (KLF15)&#x7136;&#x800C;&#xFF0C;&#x8FD9;&#x4E2A;&#x8F6C;&#x5F55;&#x56E0;&#x5B50;&#x5728;&#x5FC3;&#x808C;&#x7EA4;&#x7EF4;&#x5316;&#x4E2D;&#x7684;&#x4F5C;&#x7528;&#x6709;&#x4E0D;&#x62A5;&#x9053;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#x6211;&#x4EEC;&#x63D0;&#x4F9B;&#x8BC1;&#x636E;&#x6709;&#x529B; pro &#x809D;&#x7EA4;&#x7EF4;&#x5316;&#x4EE3;&#x7406;&#x8F6C;&#x751F;&#x957F;&#x56E0;&#x5B50;-beta1 (TGFbeta1) &#x7684;&#x65B0;&#x751F;&#x5927;&#x9F20;&#x5FC3;&#x5BA4;&#x6210;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE; (NRVFs) &#x6CBB;&#x7597;&#x5927;&#x5927;&#x51CF;&#x5C11;&#x4E86; KLF15 &#x540C;&#x65F6;&#x8BF1;&#x5BFC; pro &#x809D;&#x7EA4;&#x7EF4;&#x5316;&#x56E0;&#x5B50;&#x7ED3;&#x7F14;&#x7EC4;&#x7EC7;&#x751F;&#x957F;&#x56E0;&#x5B50;&#x7684;&#x8868;&#x8FBE;&#x3002;&#x817A;&#x75C5;&#x6BD2;&#x8868;&#x8FBE;&#x7684; KLF15 &#x6291;&#x5236; NRVFs &#x7684;&#x57FA;&#x5E95;&#x548C; TGFbeta1 &#x8BF1;&#x5BFC;&#x7ED3;&#x7F14;&#x7EC4;&#x7EC7;&#x751F;&#x957F;&#x56E0;&#x5B50;&#x8868;&#x8FBE;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x4ECE; KLF15-/-&#x5C0F;&#x9F20;&#x4E3B;&#x52A8;&#x8109;&#x52A0;&#x5BBD;&#x906D;&#x53D7;&#x5FC3;&#x7075;&#x5C55;&#x793A;&#x589E;&#x52A0;&#x7ED3;&#x7F14;&#x7EC4;&#x7EC7;&#x751F;&#x957F;&#x56E0;&#x5B50;&#x6C34;&#x5E73;&#x4E0E;&#x7EA4;&#x7EF4;&#x5316;&#x3002;&#x4ECE;&#x673A;&#x68B0;&#x7684;&#x89D2;&#x5EA6;&#x6765;&#x770B;&#xFF0C;KLF15 &#x6291;&#x5236;&#x7ED3;&#x7F14;&#x7EC4;&#x7EC7;&#x751F;&#x957F;&#x56E0;&#x5B50;&#x57FA;&#x56E0;&#x542F;&#x52A8;&#x5B50;&#x7684;&#x57FA;&#x5E95;&#x548C;&#x4ECB;&#x5BFC; TGFbeta1 &#x611F;&#x5E94;&#x3002;&#x67D3;&#x8272;&#x8D28;&#x6C89;&#x6DC0; (&#x82AF;&#x7247;) &#x548C;&#x7535;&#x6CF3;&#x8FC1;&#x79FB;&#x8F6C;&#x53D8;&#x68C0;&#x5B9A;&#x6CD5;&#x8BC1;&#x660E; KLF15 &#x6291;&#x5236;&#x6210;&#x866B; P/CAF &#x62DB;&#x8058;&#xFF0C;&#x5BF9;&#x7ED3;&#x7F14;&#x7EC4;&#x7EC7;&#x751F;&#x957F;&#x56E0;&#x5B50;&#x52A9;&#x5242;&#x4E0E;&#x5BF9; Smad3 DNA &#x7ED1;&#x5B9A;&#x6CA1;&#x6709;&#x663E;&#x8457;&#x5F71;&#x54CD;&#x3002;&#x7B26;&#x5408;&#x8FD9;&#x4E00;&#x89C2;&#x5BDF;&#xFF0C;KLF15 &#x7ED3;&#x7F14;&#x7EC4;&#x7EC7;&#x751F;&#x957F;&#x56E0;&#x5B50;&#x57FA;&#x56E0;&#x542F;&#x52A8;&#x5B50;&#x4ECB;&#x5BFC;&#x7684;&#x9547;&#x538B;&#x662F;&#x7531;&#x6551;&#x51FA; P/CAF &#x8FC7;&#x5EA6;&#x8868;&#x8FBE;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x7ED3;&#x679C;&#x6D89;&#x53CA; KLF15 &#x4F5C;&#x4E3A;&#x4E00;&#x4E2A;&#x65B0;&#x578B;&#x8D1F;&#x76D1;&#x7BA1;&#x7684;&#x7ED3;&#x7F14;&#x7EC4;&#x7EC7;&#x751F;&#x957F;&#x56E0;&#x5B50;&#x7684;&#x8868;&#x8FBE;&#x4E0E;&#x5FC3;&#x810F;&#x7EA4;&#x7EF4;&#x5316;&#x3002;

Kruppel &#x6837;&#x56E0;&#x5B50; KLF15 &#x6291;&#x5236;&#x5FC3;&#x810F;&#x6210;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#x7ED3;&#x7F14;&#x7EC4;&#x7EC7;&#x751F;&#x957F;&#x56E0;&#x5B50; &#xFF08;CTGF&#xFF09; &#x7684;&#x8868;&#x8FBE;&#x3002;

Cardiac fibrosis is a hallmark feature of pathologic remodeling of the heart in response to hemodynamic or neurohormonal stress. Accumulating evidence implicates connective tissue growth factor (CTGF) as a key mediator of this process. Our group has previously identified Kruppel-Like Factor 15 (KLF15) as an important regulator of cardiac remodeling in response to stress; however, the role of this transcription factor in cardiac fibrosis has not been reported. Here we provide evidence that treatment of neonatal rat ventricular fibroblasts (NRVFs) with the potent pro-fibrotic agent Transforming Growth Factor-beta1 (TGFbeta1) strongly reduces KLF15 expression while inducing the pro-fibrotic factor CTGF. Adenoviral overexpression of KLF15 inhibits basal and TGFbeta1-induced CTGF expression in NRVFs. Furthermore, hearts from KLF15-/- mice subjected to aortic banding exhibited increased CTGF levels and fibrosis. From a mechanistic standpoint, KLF15 inhibits basal and TGFbeta1-mediated induction of the CTGF promoter. Chromatin Immunoprecipitation (ChIP) and electrophoretic mobility shift assays demonstrate that KLF15 inhibits recruitment of the co-activator P/CAF to the CTGF promoter with no significant effect on Smad3-DNA binding. Consistent with this observation, KLF15 mediated repression of the CTGF promoter is rescued by P/CAF overexpression. Our result implicates KLF15 as a novel negative regulator of CTGF expression and cardiac fibrosis.

The Kruppel-like factor KLF15 inhibits connective tissue growth factor (CTGF) expression in cardiac fibroblasts.

Fibrose cardiaque est une fonctionnalit&eacute; caract&eacute;ristique du remodelage pathologique du coeur en r&eacute;ponse au stress h&eacute;modynamique ou neurohormonaux. Accumulation de preuves implique que le facteur de croissance du tissu conjonctif (CTGF) comme m&eacute;diateur cl&eacute; de ce processus. Notre groupe a d&eacute;j&agrave; identifi&eacute; 15 de facteur de Kruppel-Like (KLF15) comme un r&eacute;gulateur important de remodelage cardiaque en r&eacute;ponse au stress ; Cependant, le r&ocirc;le de ce facteur de transcription dans la fibrose cardiaque n&#39;a &eacute;t&eacute; signal&eacute;. Nous fournissons ici la preuve que le traitement des fibroblastes ventriculaires de rat n&eacute;onatal (NRVFs) avec le puissant agent profibrotiques Transforming Growth Factor-beta1 (TGFbeta1) r&eacute;duit fortement KLF15 expression tout en induisant le facteur profibrotiques CTGF. Ad&eacute;novirale surexpression de KLF15 inhibe l&#39;expression CTGF basale et induite par le TGFbeta1 en NRVFs. En outre, coeurs de rats soumis &agrave; un cerclage aortique KLF15-/-souris pr&eacute;sentaient une augmentation des niveaux CTGF et la fibrose. D&#39;un point de vue m&eacute;caniste, KLF15 inhibe l&#39;induction basale et TGFbeta1 par l&#39;interm&eacute;diaire du promoteur CTGF. Immunopr&eacute;cipitation de la chromatine (ChIP) et de la mobilit&eacute; &eacute;lectrophor&eacute;tique essais d&eacute;montrent que KLF15 inhibe le recrutement du co-activateur P/CAF au promoteur CTGF sans effet significatif sur la liaison Smad3-ADN. Conform&eacute;ment &agrave; cette observation, KLF15 r&eacute;pression m&eacute;di&eacute;e du promoteur CTGF est sauv&eacute;e par la surexpression de P/CAF. Notre r&eacute;sultat implique KLF15 comme un r&eacute;gulateur n&eacute;gatif roman d&#39;expression CTGF et la fibrose cardiaque.

Le Kruppel-like factor KLF15 inhibe l&#39;expression du facteur de croissance (CTGF) tissu conjonctif dans les fibroblastes cardiaques.

Kardialer Fibrose ist ein Markenzeichen-Feature von pathologischen Umbau des Herzens als Reaktion auf h&auml;modynamische oder neurohormonal Stress. Beweise sammeln bringt Bindegewebe Wachstumsfaktor (CTGF) als wichtiger Vermittler dieses Prozesses. Unsere Fraktion hat zuvor Kruppel-Like Faktor 15 (KLF15) als ein wichtiger Regulator der kardialen Umgestaltung in Reaktion auf stress gekennzeichnet. jedoch wurde die Rolle der dieser Transkriptionsfaktor bei kardialer Fibrose nicht berichtet. Hier stellen wir Hinweise darauf, dass die Behandlung von Neugeborenen Ratte ventrikul&auml;re Fibroblasten (NRVFs) mit dem potenten Pro-fibrotische Agent Transforming Growth Factor-beta1 (TGFbeta1) KLF15 Ausdruck w&auml;hrend den Pro-fibrotische Faktor CTGF induzierende stark reduziert. Adenoviral eine &Uuml;berexpression von KLF15 hemmt basal und TGFbeta1-induzierte CTGF Ausdruck in NRVFs. Dar&uuml;ber hinaus stellte Hearts aus KLF15-/-M&auml;use ausgesetzt Aorten Streifenbildung erh&ouml;hte CTGF Ebenen und Fibrose. Von einem mechanistischen Standpunkt hemmt KLF15 basale und TGFbeta1-vermittelte Induktion des Projekttr&auml;gers CTGF. Chromatin Immunopr&auml;zipitation (ChIP) und elektrophoretische Mobilit&auml;t UMSCHALT Proben zeigen, dass KLF15 hemmt die Rekrutierung von Coaktivator P/CAF f&uuml;r den CTGF-F&ouml;rderer mit keinen signifikanten Einfluss auf Smad3-DNA-Bindung. Mit dieser Feststellung KLF15 vermittelten Unterdr&uuml;ckung des Projekttr&auml;gers CTGF wird von P/CAF-&Uuml;berexpression gerettet. Unser Ergebnis steht in Verbindung mit KLF15 als neuartige negativer Regulator des CTGF Expression und kardialer Fibrose.

Der Kruppel-&auml;hnlichen Faktor KLF15 hemmt Bindegewebe Wachstumsfaktor (CTGF) Ausdruck in kardialen Fibroblasten.

Fibrosi cardiaca &egrave; una caratteristica del segno distintivo di rimodellamento patologico del cuore in risposta a stress emodinamico o neuroormonale. Accumulando prove implica il fattore di crescita del tessuto connettivo (CTGF) come mediatore chiave di questo processo. Il nostro gruppo ha identificato in precedenza Kruppel-Like fattore 15 (KLF15) come un regolatore importante del rimodellamento cardiaco in risposta allo stress; Tuttavia, il ruolo di questo fattore di trascrizione nella fibrosi cardiaca non &egrave; stato segnalato. Qui forniamo prove che il trattamento dei fibroblasti ventricolare neonatale ratto (NRVFs) con il potente agente pro-fibrotico Transforming Growth Factor-beta1 (TGFbeta1) riduce fortemente KLF15 espressione mentre inducendo il fattore pro-fibrotico CTGF. Adenovirali sovraespressione di KLF15 inibisce la espressione di CTGF basale e TGFbeta1-indotta in NRVFs. Inoltre, cuori da KLF15/topi sottoposti a banding aortica esposto aumentati livelli di CTGF e fibrosi. Dal punto di vista meccanicistico, KLF15 inibisce la induzione basale e TGFbeta1-mediata del promotore del CTGF. Immunoprecipitazione della cromatina (ChIP) e dosaggi di spostamento di mobilit&agrave; elettroforetica dimostrano che KLF15 inibisce il reclutamento del coattivatore P/CAF al promotore CTGF con alcun effetto significativo sul legame del DNA Smad3. Coerente con questa osservazione, KLF15 mediata repressione del promotore del CTGF viene salvata da iperespressione P/CAF. Il nostro risultato implica KLF15 come un romanzo regolatore negativo dell&#39;espressione CTGF e fibrosi cardiaca.

Il fattore Kruppel-come KLF15 inibisce la espressione growth factor (CTGF) tessuto connettivo nei fibroblasti cardiaci.

&#x5FC3;&#x7B4B;&#x7DDA;&#x7DAD;&#x5316;&#x75C5;&#x7406;&#x5B66;&#x7684;&#x8840;&#x884C;&#x52D5;&#x614B;&#x3084;&#x5FC3;&#x4E0D;&#x5168;&#x306E;&#x30B9;&#x30C8;&#x30EC;&#x30B9;&#x306B;&#x5FDC;&#x7B54;&#x3057;&#x3066;&#x5FC3;&#x306E;&#x6539;&#x9020;&#x306E;&#x7279;&#x5FB4;&#x3067;&#x3059;&#x3002;&#x8A3C;&#x62E0;&#x3092;&#x84C4;&#x7A4D;&#x7D50;&#x5408;&#x7D44;&#x7E54;&#x6210;&#x9577;&#x56E0;&#x5B50; (CTGF) &#x306F;&#x3001;&#x3053;&#x306E;&#x30D7;&#x30ED;&#x30BB;&#x30B9;&#x306E;&#x9375;&#x306E;&#x30E1;&#x30C7;&#x30A3;&#x30A8;&#x30FC;&#x30BF;&#x30FC;&#x3068;&#x3057;&#x3066;&#x95A2;&#x4FC2;&#x3065;&#x3051;&#x307E;&#x3059;&#x3002;&#x5F53;&#x793E;&#x30B0;&#x30EB;&#x30FC;&#x30D7;&#x306F;&#x3001;&#x4EE5;&#x524D;&#x30B9;&#x30C8;&#x30EC;&#x30B9;&#x306B;&#x5FDC;&#x3048;&#x3066;&#x5FC3;&#x81D3;&#x30EA;&#x30E2;&#x30C7;&#x30EA;&#x30F3;&#x30B0;&#x306F;&#x91CD;&#x8981;&#x306A;&#x8ABF;&#x7BC0;&#x56E0;&#x5B50;&#x3068;&#x3057;&#x3066; Kruppel-Like &#x56E0;&#x5B50; 15 (KLF15) &#x3092;&#x8B58;&#x5225;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;;&#x305F;&#x3060;&#x3057;&#x3001;&#x3053;&#x306E;&#x5FC3;&#x7B4B;&#x7DDA;&#x7DAD;&#x5316;&#x306E;&#x8EE2;&#x5199;&#x56E0;&#x5B50;&#x306E;&#x5F79;&#x5272;&#x306F;&#x5831;&#x544A;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x305B;&#x3093;&#x3002;&#x3053;&#x3053;&#x3067;&#x5F37;&#x529B;&#x306A;&#x30D7;&#x30ED;&#x7DDA;&#x7DAD;&#x30A8;&#x30FC;&#x30B8;&#x30A7;&#x30F3;&#x30C8;&#x8EE2;&#x63DB;&#x6210;&#x9577;&#x56E0;&#x5B50;-beta1 (TGFbeta1) &#x3068;&#x65B0;&#x751F;&#x5150;&#x30E9;&#x30C3;&#x30C8;&#x5FC3;&#x5BA4;&#x7DDA;&#x7DAD;&#x82BD;&#x7D30;&#x80DE; (NRVFs) &#x306E;&#x6CBB;&#x7642;&#x304C;&#x5F37;&#x304F;&#x8A98;&#x5C0E;&#x30D7;&#x30ED;&#x7DDA;&#x7DAD;&#x5316;&#x56E0;&#x5B50; CTGF &#x306A;&#x304C;&#x3089; KLF15 &#x5F0F;&#x3092;&#x6E1B;&#x5C11;&#x3055;&#x305B;&#x308B;&#x3053;&#x3068;&#x306E;&#x8A3C;&#x62E0;&#x3092;&#x63D0;&#x4F9B;&#x3057;&#x307E;&#x3059;&#x3002;&#x30A2;&#x30C7;&#x30CE; &#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x306E;&#x904E;&#x5270;&#x767A;&#x73FE; KLF15 &#x306E;&#x57FA;&#x5E95;&#x3068; TGFbeta1 &#x8A98;&#x8D77; CTGF &#x306E;&#x767A;&#x73FE; NRVFs &#x3067;&#x3092;&#x963B;&#x5BB3;&#x3057;&#x307E;&#x3059;&#x3002;&#x3055;&#x3089;&#x306B;&#x3001;&#x5FC3;&#x304B;&#x3089; KLF15/&#x30DE;&#x30A6;&#x30B9;&#x5927;&#x52D5;&#x8108;&#x30D0;&#x30F3;&#x30C7;&#x30A3;&#x30F3;&#x30B0;&#x306B;&#x53D7;&#x3051;&#x308B;&#x5897;&#x52A0; CTGF &#x30EC;&#x30D9;&#x30EB;&#x3068;&#x7DDA;&#x7DAD;&#x5316;&#x3092;&#x51FA;&#x5C55;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x6A5F;&#x68B0;&#x7684;&#x306A;&#x89B3;&#x70B9;&#x304B;&#x3089;&#x306F;&#x3001;KLF15 CTGF &#x30D7;&#x30ED;&#x30E2;&#x30FC;&#x30BF;&#x30FC;&#x306E;&#x57FA;&#x5E95;&#x3068; TGFbeta1 &#x3092;&#x4ECB;&#x3059;&#x308B;&#x8A98;&#x5C0E;&#x3092;&#x963B;&#x5BB3;&#x3057;&#x307E;&#x3059;&#x3002;&#x30AF;&#x30ED;&#x30DE;&#x30C1;&#x30F3;&#x514D;&#x75AB;&#x6C88;&#x964D; (ChIP) &#x3068;&#x96FB;&#x6C17;&#x6CF3;&#x52D5;&#x306E;&#x79FB;&#x52D5;&#x6027;&#x30B7;&#x30D5;&#x30C8;&#x8A66;&#x91D1; KLF15 &#x30B3;&#x30A2;&#x30AF;&#x30C1;&#x30D9;&#x30FC;&#x30BF;&#x30FC; P/CAF &#x306E;&#x52DF;&#x96C6;&#x3001;CTGF &#x30D7;&#x30ED;&#x30E2;&#x30FC;&#x30BF;&#x30FC; Smad3 DNA &#x7D50;&#x5408;&#x306B;&#x91CD;&#x8981;&#x306A;&#x5F71;&#x97FF;&#x3092;&#x963B;&#x5BB3;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3053;&#x306E;&#x89B3;&#x5BDF;&#x3001;KLF15 &#x306B;&#x3088;&#x3063;&#x3066;&#x4EF2;&#x4ECB;&#x3055;&#x308C;&#x305F;&#x6291;&#x5727; CTGF &#x30D7;&#x30ED;&#x30E2;&#x30FC;&#x30BF;&#x30FC;&#x306E; P/CAF overexpression &#x306B;&#x3088;&#x3063;&#x3066;&#x6551;&#x51FA;&#x3055;&#x308C;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005; &#x306E;&#x7D50;&#x679C;&#x306F; CTGF &#x306E;&#x767A;&#x73FE;&#x3068;&#x5FC3;&#x7B4B;&#x7DDA;&#x7DAD;&#x5316;&#x306E;&#x5C0F;&#x8AAC;&#x306E;&#x8CA0;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30BF;&#x3068;&#x3057;&#x3066; KLF15 &#x3092;&#x95A2;&#x4FC2;&#x3065;&#x3051;&#x307E;&#x3059;&#x3002;

&#x30AF;&#x30EB;&#x30C3;&#x30DA;&#x30EB;&#x69D8;&#x56E0;&#x5B50; KLF15 &#x7D50;&#x5408;&#x7D44;&#x7E54;&#x6210;&#x9577;&#x56E0;&#x5B50; (CTGF) &#x5F0F;&#x5FC3;&#x7B4B;&#x7DDA;&#x7DAD;&#x82BD;&#x7D30;&#x80DE;&#x3092;&#x6291;&#x5236;&#x3057;&#x307E;&#x3059;&#x3002;

&#xC2EC;&#xC7A5; &#xC12C;&#xC720; &#xC99D; pathologic hemodynamic &#xB610;&#xB294; neurohormonal &#xC2A4;&#xD2B8;&#xB808;&#xC2A4;&#xC5D0; &#xB300; &#xD55C; &#xC751;&#xB2F5;&#xC5D0;&#xC11C; &#xC2EC;&#xC7A5;&#xC758; &#xB9AC; &#xBAA8;&#xB378;&#xB9C1;&#xC758; &#xAC01; &#xC778; &#xAE30;&#xB2A5;&#xC785;&#xB2C8;&#xB2E4;. &#xC774; &#xD504;&#xB85C;&#xC138;&#xC2A4;&#xC758; &#xC8FC;&#xC694; &#xC911;&#xC7AC;&#xC790; &#xACB0;&#xD569; &#xC870;&#xC9C1; &#xC131;&#xC7A5; &#xC778;&#xC790; (CTGF)&#xC744; &#xC5F0;&#xB8E8; &#xC99D;&#xAC70;&#xB97C; &#xCD95;&#xC801;. &#xC6B0;&#xB9AC;&#xC758; &#xADF8;&#xB8F9; &#xC2A4;&#xD2B8;&#xB808;&#xC2A4;;&#xC5D0; &#xB300; &#xD55C; &#xC751;&#xB2F5; &#xC2EC;&#xC7A5; &#xB9AC; &#xBAA8;&#xB378;&#xB9C1;&#xC758; &#xC911;&#xC694; &#xD55C; &#xB808; &#xADE4; &#xB808;&#xC774; &#xD130;&#xB85C; &#xC774;&#xC804;&#xC5D0; Kruppel-Like &#xC694;&#xC18C; 15 (KLF15)&#xB97C; &#xBC1C;&#xACAC; &#xD588;&#xB2E4; &#xADF8;&#xB7EC;&#xB098;, &#xC2EC;&#xC7A5; &#xC12C;&#xC720; &#xC99D;&#xC5D0;&#xC774; &#xB179;&#xC74C; &#xBC29;&#xC1A1; &#xC694;&#xC778;&#xC758; &#xC5ED;&#xD560;&#xC740; &#xB418;&#xC9C0; &#xBCF4;&#xACE0; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC5EC;&#xAE30;&#xC5D0; &#xC6B0;&#xB9AC;&#xAC00; &#xCE58;&#xB8CC; &#xC2E0;&#xC0DD;&#xC544; &#xC950; &#xC2EC; &#xC2E4; &#xC12C;&#xC720; &#xC544; &#xC138;&#xD3EC; (NRVFs)&#xC758; &#xAC15;&#xB825;&#xD55C; &#xD504;&#xB85C; fibrotic &#xC5D0;&#xC774;&#xC804;&#xD2B8; &#xBCC0;&#xD615; &#xC131;&#xC7A5; &#xC778;&#xC790; beta1 (TGFbeta1)&#xB97C; &#xAC15;&#xB825; &#xD558; &#xAC8C; &#xD504;&#xB85C; fibrotic &#xC694;&#xC18C; CTGF&#xC744; &#xC720;&#xB3C4; &#xD558;&#xB294; &#xB3D9;&#xC548; KLF15 &#xC2DD; &#xAC10;&#xC18C; &#xC99D;&#xAC70; &#xC81C;&#xACF5;. Adenoviral overexpression klf15&#xC758; Nrvfs&#xC5D0; &#xAE30;&#xC800;&#xC640; Tgfbeta1&#xC744; &#xC774;&#xC6A9;&#xD55C; CTGF &#xC2DD;&#xC744; &#xC5B5;&#xC81C; &#xD55C;&#xB2E4;. &#xB610;&#xD55C;, KLF15-/-&#xC0DD;&#xC950; &#xB300;&#xB3D9;&#xB9E5; banding&#xC744; &#xBCF5;&#xC885;&#xC5D0;&#xC11C; &#xB9C8;&#xC74C; &#xC804;&#xC2DC; &#xC99D;&#xAC00; CTGF &#xC218;&#xC900; &#xBC0F; &#xC12C;&#xC720; &#xC99D;. &#xAE30;&#xACC4; &#xB860; &#xC801;&#xC778; &#xAD00;&#xC810;&#xC5D0;&#xC11C; KLF15 CTGF &#xBC1C;&#xAE30;&#xC778;&#xC758; &#xAE30;&#xC800; &#xBC0F; TGFbeta1 &#xC911;&#xC7AC; &#xC720;&#xB3C4;&#xB97C; &#xC5B5;&#xC81C; &#xD55C;&#xB2E4;. Chromatin Immunoprecipitation (&#xCE69;) &#xBC0F; &#xC804;&#xAE30; &#xC774;&#xB3D9; &#xAE30;&#xB3D9;&#xC131; &#xAD50;&#xB300; &#xBD84;&#xC11D; &#xC2E4;&#xD5D8; KLF15 Smad3 DNA &#xBC14;&#xC778;&#xB529;&#xC5D0; &#xC0C1;&#xB2F9;&#xD55C; &#xC601;&#xD5A5;&#xC744; CTGF &#xBC1C;&#xAE30;&#xC778;&#xC744; &#xBC29;&#xC1A1; P/CAF&#xC758; &#xCC44;&#xC6A9;&#xC744; &#xC5B5;&#xC81C; &#xD558;&#xB294; &#xBC29;&#xBC95;&#xC744; &#xBCF4;&#xC5EC; &#xC90D;&#xB2C8;&#xB2E4;. &#xC774; &#xAD00;&#xCC30;, klf15&#xC640; &#xC77C;&#xCE58; CTGF &#xBC1C;&#xAE30;&#xC778;&#xC758; &#xC911;&#xC7AC; &#xC5B5;&#xC555; P/CAF overexpression&#xC5D0; &#xC758;&#xD574; &#xAD6C;&#xCD9C; &#xB429;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xC758; &#xACB0;&#xACFC; CTGF &#xC2DD; &#xBC0F; &#xC2EC;&#xC7A5; &#xC12C;&#xC720; &#xC99D;&#xC758; &#xC18C;&#xC124; &#xB124;&#xAC70;&#xD2F0;&#xBE0C; &#xB808; &#xADE4; &#xB808;&#xC774; &#xD130;&#xB85C; klf15&#xB97C; &#xC5F0;&#xB8E8;.

Kruppel &#xAC19;&#xC740; &#xC778;&#xC790; KLF15 &#xC2EC;&#xC7A5; &#xC12C;&#xC720; &#xC544; &#xC138;&#xD3EC;&#xC5D0; &#xACB0;&#xD569; &#xC870;&#xC9C1; &#xC131;&#xC7A5; &#xC778;&#xC790; (CTGF) &#xC2DD;&#xC744; &#xC5B5;&#xC81C; &#xD55C;&#xB2E4;.

Fibrosis cardiaca es una caracter&iacute;stica de sello de remodelaci&oacute;n patol&oacute;gica del coraz&oacute;n en respuesta al estr&eacute;s hemodin&aacute;mico o neurohormonal. La acumulaci&oacute;n de pruebas implica el factor de crecimiento de tejido conectivo (CTGF) como un mediador clave de este proceso. Nuestro grupo ha identificado previamente Kruppel-Like Factor 15 (KLF15) como un importante regulador de la remodelaci&oacute;n cardiaca en respuesta al estr&eacute;s; sin embargo, el papel de este factor de transcripci&oacute;n en la fibrosis cardiaca no se ha divulgado. Aqu&iacute; proporcionamos evidencia que el tratamiento de fibroblastos ventricular de rata neonatal (NRVFs) con el potente agente pro-fibr&oacute;tico Transforming Growth Factor-beta1 (TGFbeta1) reduce fuertemente KLF15 expresi&oacute;n mientras que inducen el factor pro-fibr&oacute;tico CTGF. Adenoviral sobreexpresi&oacute;n de KLF15 inhibe la expresi&oacute;n de CTGF basal y TGFbeta1-inducida en NRVFs. Adem&aacute;s, corazones de KLF15-/-ratones sometidos a bandas a&oacute;rtica exhibieron mayores niveles CTGF y fibrosis. Desde un punto de vista mecanicista, KLF15 inhibe basal y TGFbeta1 mediada por la inducci&oacute;n del promotor CTGF. Inmunoprecipitaci&oacute;n de cromatina (ChIP) y movilidad electrofor&eacute;tica cambio ensayos demuestran que KLF15 inhibe el reclutamiento de la coactivador P/CAF al promotor CTGF con ning&uacute;n efecto significativo sobre Smad3-DNA obligatorio. Consistente con esta observaci&oacute;n, KLF15 represi&oacute;n mediada del promotor CTGF es rescatada por la sobreexpresi&oacute;n de P/CAF. Nuestro resultado implica KLF15 como un regulador negativo novela de expresi&oacute;n CTGF y fibrosis cardiaca.

El factor de Kruppel-like KLF15 inhibe la expresi&oacute;n del factor de crecimiento (CTGF) de tejido conectivo en fibroblastos cardiacos.

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) have been discovered in several cancer types and cause the neurometabolic syndrome D2-hydroxyglutaric aciduria (D2HGA). The mutant enzymes exhibit neomorphic activity resulting in production of D2-hydroxyglutaric acid (D-2HG). To study the pathophysiological consequences of the accumulation of D-2HG, we generated transgenic mice with conditionally activated IDH2(R140Q) and IDH2(R172K) alleles. Global induction of mutant IDH2 expression in adults resulted in dilated cardiomyopathy, white matter abnormalities throughout the central nervous system (CNS), and muscular dystrophy. Embryonic activation of mutant IDH2 resulted in more pronounced phenotypes, including runting, hydrocephalus, and shortened life span, recapitulating the abnormalities observed in D2HGA patients. The diseased hearts exhibited mitochondrial damage and glycogen accumulation with a concordant up-regulation of genes involved in glycogen biosynthesis. Notably, mild cardiac hypertrophy was also observed in nude mice implanted with IDH2(R140Q)-expressing xenografts, suggesting that 2HG may potentially act in a paracrine fashion. Finally, we show that silencing of IDH2(R140Q) in mice with an inducible transgene restores heart function by lowering 2HG levels. Together, these findings indicate that inhibitors of mutant IDH2 may be beneficial in the treatment of D2HGA and suggest that 2HG produced by IDH mutant tumors has the potential to provoke a paraneoplastic condition.

D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice.

In response to injury, the rodent heart is capable of virtually full regeneration via cardiomyocyte proliferation early in life. This regenerative capacity, however, is diminished as early as 1 week postnatal and remains lost in adulthood. The mechanisms that dictate postinjury cardiomyocyte proliferation early in life remain unclear.

Sudeshna Fisch

Cardiac Muscle Research Labratory,
Cardiovascular Division,
Brigham and Women’s Hospital,
Cardiac Muscle Research Labratory, Cardiovascular Division, Brigham and Women’s Hospital

Harvard Medical School

Assessment of Right Ventricular Structure and Function in Mouse Model of Pulmonary Artery Constriction by Transthoracic Echocardiography

Early Detection of Drug-Induced Renal Hemodynamic Dysfunction Using Sonographic Technology in Rats

Ultrasound Based Assessment of Coronary Artery Flow and Coronary Flow Reserve Using the Pressure Overload Model in Mice

High-Frequency Ultrasound Echocardiography to Assess Zebrafish Cardiac Function

Sudeshna Fisch

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Cardiac Muscle Research Labratory,Cardiovascular Division,Brigham and Women’s Hospital,Cardiac Muscle Research Labratory, Cardiovascular Division, Brigham and Women’s Hospital

Harvard Medical School

Assessment of Right Ventricular Structure and Function in Mouse Model of Pulmonary Artery Constriction by Transthoracic Echocardiography

Early Detection of Drug-Induced Renal Hemodynamic Dysfunction Using Sonographic Technology in Rats

Ultrasound Based Assessment of Coronary Artery Flow and Coronary Flow Reserve Using the Pressure Overload Model in Mice

High-Frequency Ultrasound Echocardiography to Assess Zebrafish Cardiac Function

Cardiac Muscle Research Labratory,
Cardiovascular Division,
Brigham and Women’s Hospital,
Cardiac Muscle Research Labratory, Cardiovascular Division, Brigham and Women’s Hospital