Induction of Myocardial Infarction and Myocardial Ischemia-Reperfusion Injury in Mice

Acute myocardial infarction is a common cardiovascular disease with high mortality. Myocardial reperfusion injury can counteract the beneficial effects of ...

Huazhong University of Science and Technology

&#x539F;&#x53D1;&#x6027;&#x9AD8;&#x8840;&#x538B;&#x662F;&#x4E00;&#x79CD;&#x6162;&#x6027;&#x75BE;&#x75C5;&#x53D1;&#x75C5;&#x7387;&#x9AD8;&#xFF0C;&#x4E0E;&#x53CA;&#x8840;&#x538B;&#x63A7;&#x5236;&#x7387;&#x662F;&#x8FDC;&#x4E0D;&#x4EE4;&#x4EBA;&#x6EE1;&#x610F;&#x7684;&#x3001; &#x4E16;&#x754C;&#x8303;&#x56F4;&#x5185;&#x3002;&#x75AB;&#x82D7;&#x63A5;&#x79CD;&#x63D0;&#x4F9B;&#x4E00;&#x4E2A;&#x5927;&#x6709;&#x53EF;&#x4E3A;&#x7684;&#x529E;&#x6CD5;&#x6CBB;&#x7597;&#x9AD8;&#x8840;&#x538B;&#x548C;&#x6539;&#x8FDB;&#x6CD5;&#x89C4;&#x9075;&#x4ECE;&#x6027;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;ATRQ&beta;-001 &#x75AB;&#x82D7;&#xFF0C;&#x4E00;&#x79CD;&#x80BD; (ATR-001) &#x6E90;&#x81EA;&#x4EBA;&#x7C7B;&#x8840;&#x7BA1;&#x7D27;&#x5F20;&#x7D20; &#xFF08;Ang II&#xFF09; II &#x53D7;&#x4F53;&#x7C7B;&#x578B; 1 Q&beta; &#x566C;&#x83CC;&#x4F53;&#x75C5;&#x6BD2;&#x6837;&#x9897;&#x7C92;&#x4E0E;&#x5171;&#x8F6D;&#xFF0C;&#x7F16;&#x5199;&#x548C;&#x9AD8;&#x8840;&#x538B;&#x75C5;&#x7684;&#x52A8;&#x7269;&#x6A21;&#x578B;&#x8FDB;&#x884C;&#x8BA1;&#x7B97;&#x3002;ATRQ&beta;-001 &#x75AB;&#x82D7;&#x5927;&#x5927;&#x964D;&#x4F4E;&#x8840;&#x538B;&#x7684;&#x8840;&#x7BA1;&#x7D27;&#x5F20;&#x7D20; II &#x8BF1;&#x5BFC;&#x9AD8;&#x8840;&#x538B;&#x5C0F;&#x9F20;&#x8FBE; 35 mm Hg (143&plusmn;4 &#x4E0E; 178&plusmn;6 mm Hg &#xFF1B;P = 0.005) &#x548C;&#x81EA;&#x53D1;&#x6027;&#x9AD8;&#x8840;&#x538B;&#x5927;&#x9F20;&#x7684;&#x8FBE; 19 mm Hg (173&plusmn;2 &#x4E0E; 192&plusmn;3 mm Hg &#xFF1B;P = 0.003&#xFF09; &#x548C;&#x963B;&#x6B62;&#x91CD;&#x5851;&#x8106;&#x5F31;&#x9AD8;&#x8840;&#x538B;&#x9776;&#x5668;&#x5B98;&#x3002;&#x6CA1;&#x6709;&#x660E;&#x663E;&#x7684;&#x53CD;&#x9988;&#x6FC0;&#x6D3B;&#x5FAA;&#x73AF;&#x6216;&#x5C40;&#x90E8;&#x80BE;&#x7D20;-&#x8840;&#x7BA1;&#x7D27;&#x5F20;&#x7D20;&#x7CFB;&#x7EDF;&#x88AB;&#x89C2;&#x5BDF;&#x5230;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x6CA1;&#x6709;&#x91CD;&#x5927;&#x514D;&#x75AB;&#x4ECB;&#x5BFC;&#x635F;&#x4F24;&#x5DF2;&#x63A5;&#x79CD;&#x75AB;&#x82D7;&#x7684;&#x9AD8;&#x8840;&#x538B;&#x3001; &#x9AD8;&#x8840;&#x538B;&#x6027;&#x52A8;&#x7269;&#x4E2D;&#x68C0;&#x6D4B;&#x5230;&#x3002;&#x6297;-ATR-001 &#x6297;&#x4F53;&#x7684;&#x534A;&#x8870;&#x671F;&#x662F; 14.4 &#x5929;&#xFF0C;&#x8D85;&#x8D8A;&#x73B0;&#x6709;&#x7684;&#x5316;&#x5B66;&#x836F;&#x7269;&#x3002;&#x5728;&#x8BD5;&#x7BA1;&#x91CC;&#xFF0C;&#x53CD;-ATR-001 &#x6297;&#x4F53;&#x4E13;&#x95E8;&#x7ED1;&#x5B9A;&#x5230;&#x8840;&#x7BA1;&#x7D27;&#x5F20;&#x7D20; II &#x53D7;&#x4F53;&#x7C7B;&#x578B; 1 &#x548C;&#x6291;&#x5236; Ca(2+) &#x4F9D;&#x8D56;&#x4FE1;&#x53F7;&#x8F6C;&#x5BFC;&#x4E8B;&#x4EF6;&#xFF0C;&#x5176;&#x4E2D;&#x5305;&#x62EC;&#x86CB;&#x767D;&#x6FC0;&#x9176; C &alpha; &#x6613;&#x4F4D;&#xFF0C;&#x78F7;&#x9178;&#x5316;&#x7EC6;&#x80DE;&#x5916;&#x4FE1;&#x53F7;&#x8C03;&#x8282;&#x6FC0;&#x9176; 1/2 (72%&#x51CF;&#x5C11; &#xFF1B;P = 0.013&#xFF09;&#xFF0C;&#x548C;&#x80DE;&#x5185;&#x7ECF;&#x9AD8;&#x7A0B; (68%&#x51CF;&#x5C11; &#xFF1B;P = 0.017) &#x8BF1;&#x5BFC;&#x7684;&#x8840;&#x7BA1;&#x7D27;&#x5F20;&#x7D20; II&#xFF0C;&#x4F46;&#x4E0D;&#x6291;&#x5236;&#x8840;&#x7BA1;&#x7D27;&#x5F20;&#x7D20; II &#x53D7;&#x4F53;&#x7ED3;&#x5408;&#x3002;&#x6700;&#x540E;&#xFF0C;ATRQ&beta;-001 &#x75AB;&#x82D7;&#x964D;&#x4F4E;&#x8840;&#x538B;&#x7684;&#x8840;&#x7BA1;&#x7D27;&#x5F20;&#x7D20; II &#x8BF1;&#x5BFC;&#x9AD8;&#x8840;&#x538B;&#x5C0F;&#x9F20;&#x548C;&#x81EA;&#x53D1;&#x6027;&#x9AD8;&#x8840;&#x538B;&#x5927;&#x9F20;&#x6709;&#x6548;&#x5730;&#x901A;&#x8FC7;&#x51CF;&#x5C11;&#x538B;&#x529B;&#x53CD;&#x5E94;&#x548C;&#x6291;&#x5236;&#x8840;&#x7BA1;&#x7D27;&#x5F20;&#x7D20; II &#x7531;&#x53D1;&#x8D77;&#x7684;&#x4FE1;&#x53F7;&#x8F6C;&#x5BFC;&#x3002;&#x56E0;&#x6B64;&#xFF0C;ATRQ&beta;-001 &#x75AB;&#x82D7;&#x53EF;&#x80FD;&#x63D0;&#x4F9B;&#x5C0F;&#x8BF4;&#x548C;&#x539F;&#x53D1;&#x6027;&#x9AD8;&#x8840;&#x538B;&#x6CBB;&#x7597;&#x7684;&#x65B0;&#x65B9;&#x6CD5;&#x3002;

&#x6709;&#x6548;&#x6027;&#x548C;&#x5B89;&#x5168;&#x6027;&#x7684;&#x8840;&#x7BA1;&#x7D27;&#x5F20;&#x7D20; II 1 &#x578B;&#x53D7;&#x4F53;&#x5728;&#x9AD8;&#x8840;&#x538B;&#x52A8;&#x7269;&#x4E2D;&#x7684;&#x6CBB;&#x7597;&#x6027;&#x75AB;&#x82D7;&#x3002;

Primary hypertension is a chronic disease with high morbidity, and the rate of controlled blood pressure is far from satisfactory, worldwide. Vaccination provides a promising approach for treatment of hypertension and improvement in compliance. Here, the ATRQÎ²-001 vaccine, a peptide (ATR-001) derived from human angiotensin II (Ang II) receptor type 1 conjugated with QÎ² bacteriophage virus-like particles, was developed and evaluated in animal models of hypertension. The ATRQÎ²-001 vaccine significantly decreased the blood pressure of Ang II-induced hypertensive mice up to 35 mm Hg (143Â±4 versus 178Â±6 mm Hg; P=0.005) and that of spontaneously hypertensive rats up to 19 mm Hg (173Â±2 versus 192Â±3 mm Hg; P=0.003) and prevented remodeling of vulnerable hypertensive target organs. No obvious feedback activation of circulating or local renin-angiotensin system was observed. Additionally, no significant immune-mediated damage was detected in vaccinated hypertensive and nonhypertensive animals. The half-life of the anti-ATR-001 antibody was 14.4 days, surpassing that of existing chemical drugs. In vitro, the anti-ATR-001 antibody specifically bound to Ang II receptor type 1 and inhibited Ca(2+)-dependent signal transduction events, including protein kinase C-Î± translocation, extracellular signal-regulated kinase 1/2 phosphorylation (72% decrease; P=0.013), and elevation of intracellular Ca(2+) (68% decrease; P=0.017) induced by Ang II, but without inhibiting Ang II binding to the receptor. In conclusion, the ATRQÎ²-001 vaccine decreased the blood pressure of Ang II-induced hypertensive mice and spontaneously hypertensive rats effectively through diminishing the pressure response and inhibiting signal transduction initiated by Ang II. Thus, the ATRQÎ²-001 vaccine may provide a novel and promising method for the treatment of primary hypertension.

Effectiveness and Safety of a Therapeutic Vaccine Against Angiotensin II Receptor Type 1 in Hypertensive Animals.

L&#39;hypertension art&eacute;rielle essentielle est une maladie chronique avec une morbidit&eacute; &eacute;lev&eacute;e et le taux de pression art&eacute;rielle contr&ocirc;l&eacute;e est loin d&#39;&ecirc;tre satisfaisante, dans le monde entier. La vaccination fournit une approche prometteuse pour le traitement de l&#39;hypertension et l&#39;am&eacute;lioration en conformit&eacute;. Ici, le vaccin ATRQ&beta;-001, un peptide (ATR-001) d&eacute;riv&eacute; du type de r&eacute;cepteur humain de l&#39;angiotensine II (Ang II) 1 conjugu&eacute; avec Q&beta; bact&eacute;riophage Pseudo-particules virales, a &eacute;t&eacute; con&ccedil;u et &eacute;valu&eacute; dans des mod&egrave;les animaux d&#39;hypertension. Le vaccin ATRQ&beta;-001 a consid&eacute;rablement diminu&eacute; la pression sanguine des souris induite par l&#39;Ang II hypertensives jusqu&#39;&agrave; 35 mm de Hg (143&plusmn;4 contre 178&plusmn;6 mm Hg ; P = 0,005) et celle des rats spontan&eacute;ment hypertendus jusqu&#39;&agrave; 19 mm Hg (173&plusmn;2 contre 192&plusmn;3 mm Hg ; P = 0,003) et emp&ecirc;ch&eacute; de remodelage des organes cibles vuln&eacute;rables hypertendus. Aucune activation de r&eacute;troaction &eacute;vidente de la circulation ou le syst&egrave;me r&eacute;nine-angiotensine local a &eacute;t&eacute; observ&eacute;e. En outre, aucun dommage immunitaire important a &eacute;t&eacute; d&eacute;tect&eacute; chez les animaux vaccin&eacute;s, hypertendus et non-hypertendus. La demi-vie de l&#39;anticorps anti-RTA-001 a &eacute;t&eacute; de 14,4 jours, surpassant celui de drogues chimiques existantes. In vitro, l&#39;anticorps anti-RTA-001 li&eacute; &agrave; l&#39;Ang II receptor type 1 sp&eacute;cifiquement et inhibe les &eacute;v&eacute;nements de transduction de signal Ca(2+)-d&eacute;pendante, y compris la translocation de prot&eacute;ine kinase C-&alpha;, phosphorylation extracellulaire signal-regulated kinase 1/2 (baisse de 72 % ; P = 0,013) et l&#39;&eacute;l&eacute;vation de Ca(2+) intracellulaire (diminution de 68 % ; P = 0,017) induite par l&#39;Ang II, mais sans inhiber la fixation au r&eacute;cepteur de l&#39;Ang II. En conclusion, le vaccin ATRQ&beta;-001 a diminu&eacute; la pression sanguine des souris induite par l&#39;Ang II hypertensive rats et spontan&eacute;ment hypertendus efficacement par le biais de diminuer la r&eacute;ponse de la pression et en inhibant la transduction du signal lanc&eacute;e par l&#39;Ang II. Ainsi, le vaccin ATRQ&beta;-001 peut fournir un roman et une m&eacute;thode prometteuse pour le traitement de l&#39;hypertension art&eacute;rielle essentielle.

Efficacit&eacute; et l&#39;innocuit&eacute; d&#39;un vaccin th&eacute;rapeutique contre l&#39;angiotensine II Receptor Type 1 chez les animaux hypertensifs.

Prim&auml;re Hypertonie ist eine chronische Erkrankung mit hoher Morbidit&auml;t und die Rate der kontrollierten Blutdruck ist weit von zufriedenstellende, weltweit. Impfung bietet einen viel versprechenden Ansatz zur Behandlung von Bluthochdruck und Verbesserung in &Uuml;bereinstimmung. Hier die ATRQ&beta;-001-Impfstoff, ein Peptid (ATR-001) abgeleitet, von menschlichen Angiotensin II (Ang II) Rezeptor Typ 1 mit Q&beta; Bakteriophage virus&auml;hnliche Partikel konjugierten, entwickelt und evaluiert in Tiermodellen der Hypertonie. Der ATRQ&beta;-001-Impfstoff deutlich abgenommen, den Blutdruck von Ang II-induzierte Hypertensive M&auml;use bis zu 35 mm Hg (143&plusmn;4 gegen 178&plusmn;6 mmHg; P = 0.005) und der spontan Hypertensive Ratten bis zu 19 mm Hg (173&plusmn;2 gegen 192&plusmn;3 mmHg; P = 0,003) und Umbau des gef&auml;hrdeten Hypertensive Zielorgane verhindert. Keine offensichtliche R&uuml;ckmeldungen-Aktivierung des zirkulierenden oder lokalen Renin-Angiotensin-Aldosteron-System wurde beobachtet. Dar&uuml;ber hinaus wurde keine signifikante immunvermittelte Sch&auml;den bei geimpften Hypertensive und Nonhypertensive erkannt. Die Halbwertszeit des Antik&ouml;rpers Anti-ATR-001 war 14,4 Tage &uuml;bertraf die der vorhandenen chemischen Drogen. In-vitro-der Anti-ATR-001-Antik&ouml;rper speziell an Ang II Rezeptor Typ 1 gebunden und gehemmt Ca(2+)-abh&auml;ngige Signaltransduktion Ereignisse, einschlie&szlig;lich Protein-Kinase C-&alpha;-Translokation, extrazellul&auml;re Signal-regulierte Kinase 1/2-Phosphorylierung (72 % Abnahme; P = 0,013), und Erh&ouml;hung des intrazellul&auml;ren Ca(2+) (68 % Abnahme; P = 0,017) induziert durch Ang II, aber ohne Hemmung Ang II-Bindung an den Rezeptor. Abschlie&szlig;end ging der ATRQ&beta;-001-Impfstoff den Blutdruck von Ang II-induzierte Hypertensive M&auml;use und spontan Hypertensive Ratten effektiv durch Verminderung der Druck-Antwort und Hemmung der Signaltransduktion von Ang II initiiert. Somit kann der ATRQ&beta;-001-Impfstoff eine neuartige und vielversprechende Methode zur Behandlung der prim&auml;ren Hypertonie bieten.

Wirksamkeit und Sicherheit von ein therapeutischer Impfstoff gegen Angiotensin II Rezeptor Typ 1 in Hypertensive Tiere.

L&#39;ipertensione primaria &egrave; una malattia cronica con elevata morbilit&agrave;, e il tasso di pressione sanguigna controllata &egrave; lontano da tutto il mondo, soddisfacente. Vaccinazione fornisce un approccio promettente per il trattamento dell&#39;ipertensione e miglioramento in conformit&agrave;. Qui, il vaccino ATRQ&beta;-001, un peptide (ATR-001) derivato da umano dell&#39;angiotensina II (Ang II) del recettore tipo 1 coniugato con particelle virus-simili di Q&beta; del batteriofago, sviluppato e valutato in modelli animali di ipertensione. Il vaccino ATRQ&beta;-001 &egrave; diminuito significativamente la pressione sanguigna di topi ipertesi indotta da Ang II fino a 35 mm Hg (143&plusmn;4 versus 178&plusmn;6 mm Hg; P = 0,005) e che spontaneamente ratti ipertesi fino a 19 mm Hg (173&plusmn;2 versus 192&plusmn;3 mm Hg; P = 0,003) e ha impedito che ritocca di organi bersaglio vulnerabile ipertesi. Nessuna attivazione feedback evidente del circolante o sistema renina-angiotensina locale &egrave; stata osservata. Inoltre, &egrave; stato rilevato alcun danno significativo immuno-mediata negli animali vaccinati ipertesi e nonhypertensive. L&#39;emivita dell&#39;anticorpo anti-ATR-001 era 14,4 giorni, superando quella di farmaci chimici esistenti. In vitro, l&#39;anticorpo anti-ATR-001 specificamente associato a Ang II recettore di tipo 1 e inibito Ca(2+)-dipendente segnale trasduzione eventi, tra cui una proteina chinasi C-&alpha; traslocazione, fosforilazione della chinasi segnale-regolata extracellulare 1/2 (72% riduzione; P = 0,013) e l&#39;elevazione del Ca(2+) intracellulare (diminuzione del 68%; P = 0,017) indotta da Ang II, ma senza inibizione associazione Ang II al recettore. In conclusione, il vaccino ATRQ&beta;-001 &egrave; diminuita la pressione sanguigna e spontaneamente ipertesi indotta da Ang II topi ratti ipertesi efficacemente attraverso la diminuzione della risposta di pressione e inibendo la trasduzione del segnale iniziata da Ang II. Cos&igrave;, il vaccino ATRQ&beta;-001 pu&ograve; fornire un romanzo e un metodo promettente per il trattamento dell&#39;ipertensione primaria.

L&#39;efficacia e la sicurezza di un vaccino terapeutico contro il recettore di angiotensina II tipo 1 negli animali ipertesi.

&#x539F;&#x767A;&#x6027;&#x9AD8;&#x8840;&#x5727;&#x306F;&#x9AD8;&#x3044;&#x7F79;&#x60A3;&#x7387;&#x3068;&#x6162;&#x6027;&#x75BE;&#x60A3;&#x3068;&#x8840;&#x5727;&#x5236;&#x5FA1;&#x7387;&#x306F;&#x9060;&#x304F;&#x304B;&#x3089;&#x3067;&#x3059;&#x6E80;&#x8DB3;&#x306E;&#x3044;&#x304F;&#x3001;&#x4E16;&#x754C;&#x4E2D;&#x3002;&#x4E88;&#x9632;&#x63A5;&#x7A2E;&#x6709;&#x671B;&#x306A;&#x30A2;&#x30D7;&#x30ED;&#x30FC;&#x30C1;&#x6CBB;&#x7642;&#x9AD8;&#x8840;&#x5727;&#x3068;&#x6539;&#x5584;&#x306E;&#x305F;&#x3081;&#x306E;&#x30B3;&#x30F3;&#x30D7;&#x30E9;&#x30A4;&#x30A2;&#x30F3;&#x30B9;&#x3092;&#x63D0;&#x4F9B;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;ATRQ&beta;-001 &#x30EF;&#x30AF;&#x30C1;&#x30F3; &#x30DA;&#x30D7;&#x30C1;&#x30C9; (ATR-001) &#x304B;&#x3089;&#x6D3E;&#x751F;&#x3057;&#x305F;&#x4EBA;&#x9593;&#x30A2;&#x30F3;&#x30B8;&#x30AA;&#x30C6;&#x30F3;&#x30B7;&#x30F3; (Ang II) &#x53D7;&#x5BB9;&#x4F53;&#x30BF;&#x30A4;&#x30D7; 1 &#x304C; Q&beta; &#x30D5;&#x30A1;&#x30FC;&#x30B8; &#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x69D8;&#x7C92;&#x5B50;&#x306E;&#x5171;&#x5F79;&#x3001;&#x3060;&#x3063;&#x305F;&#x3001;&#x304A;&#x3088;&#x3073;&#x958B;&#x767A;&#x3057;&#x305F;&#x9AD8;&#x8840;&#x5727;&#x75C7;&#x306E;&#x52D5;&#x7269;&#x30E2;&#x30C7;&#x30EB;&#x3067;&#x8A55;&#x4FA1;&#x3002;ATRQ&beta;-001 &#x30EF;&#x30AF;&#x30C1;&#x30F3;&#x6709;&#x610F;&#x306B; Ang II &#x8A98;&#x8D77;&#x9AD8;&#x8840;&#x5727;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x8840;&#x5727; 35 mm Hg &#xFF08;143&plusmn;4 &#x5BFE; 178&plusmn;6 &#x30DF;&#x30EA;&#x30E1;&#x30FC;&#x30C8;&#x30EB; Hg;P = 0.005&#xFF09; &#x304A;&#x3088;&#x3073;&#x81EA;&#x7136;&#x767A;&#x75C7;&#x9AD8;&#x8840;&#x5727;&#x30E9;&#x30C3;&#x30C8;&#x306E; 19 mm Hg &#xFF08;173&plusmn;2 &#x5BFE; 192&plusmn;3 &#x30DF;&#x30EA;&#x30E1;&#x30FC;&#x30C8;&#x30EB; Hg;P = 0.003) &#x8106;&#x5F31;&#x6027;&#x9AD8;&#x8840;&#x5727;&#x306E;&#x6A19;&#x7684;&#x81D3;&#x5668;&#x306E;&#x6539;&#x9020;&#x3092;&#x9632;&#x6B62;&#x3002;&#x5FAA;&#x74B0;&#x306E;&#x660E;&#x767D;&#x306A;&#x30D5;&#x30A3;&#x30FC;&#x30C9;&#x30D0;&#x30C3;&#x30AF;&#x6D3B;&#x6027;&#x5316;&#x307E;&#x305F;&#x306F;&#x30ED;&#x30FC;&#x30AB;&#x30EB; &#x30EC;&#x30CB;&#x30F3;-&#x30A2;&#x30F3;&#x30B8;&#x30AA;&#x30C6;&#x30F3;&#x30B7;&#x30F3;&#x7CFB;&#x304C;&#x89B3;&#x5BDF;&#x3055;&#x308C;&#x307E;&#x305B;&#x3093;&#x3067;&#x3057;&#x305F;&#x3002;&#x3055;&#x3089;&#x306B;&#x3001;&#x30EF;&#x30AF;&#x30C1;&#x30F3;&#x63A5;&#x7A2E;&#x306E;&#x9AD8;&#x8840;&#x5727;&#x3068; nonhypertensive &#x52D5;&#x7269;&#x306E;&#x514D;&#x75AB;&#x306E;&#x91CD;&#x8981;&#x306A;&#x640D;&#x50B7;&#x306F;&#x8A8D;&#x3081;&#x3089;&#x308C;&#x306A;&#x304B;&#x3063;&#x305F;&#x3002;&#x30A2;&#x30F3;&#x30C1; ATR 001 &#x6297;&#x4F53;&#x306E;&#x534A;&#x6E1B;&#x671F;&#x306F; 14.4 &#x89AA;&#x52DD;&#x308A;&#x65E2;&#x5B58;&#x5316;&#x5B66;&#x85AC;&#x5264;&#x306E;&#x65E5;&#x3060;&#x3063;&#x305F;&#x3002;In vitro &#x6297; ATR 001 &#x6297;&#x4F53;&#x5177;&#x4F53;&#x7684; Ang II &#x53D7;&#x5BB9;&#x4F53;&#x30BF;&#x30A4;&#x30D7; 1 &#x30D0;&#x30A4;&#x30F3;&#x30C9;&#x3057;&#x3001;&#x86CB;&#x767D;&#x8CEA;&#x30AD;&#x30CA;&#x30FC;&#x30BC; C &alpha; &#x8EE2;&#x6D41;, &#x7D30;&#x80DE;&#x5916;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x8ABF;&#x7BC0;&#x30AD;&#x30CA;&#x30FC;&#x30BC; 1/2 &#x30EA;&#x30F3;&#x9178;&#x5316; &#xFF08;72 &#xFF05; &#x6E1B;; &#x3092;&#x542B;&#x3080; Ca(2+) &#x4F9D;&#x5B58;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x30A4;&#x30D9;&#x30F3;&#x30C8;&#x3092;&#x6291;&#x5236;P &#x3007;&#x30FB;&#x3007;&#x4E00;&#x4E09; =)&#x3001;&#x304A;&#x3088;&#x3073;&#x7D30;&#x80DE;&#x5185;&#x30AB;&#x30EB;&#x30B7;&#x30A6;&#x30E0;&#x306E;&#x6A19;&#x9AD8; &#xFF08;68 &#xFF05; &#x6E1B;;P = 0.017) Ang II &#x7D50;&#x5408;&#x53D7;&#x5BB9;&#x4F53;&#x3092;&#x963B;&#x5BB3;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x306A;&#x304F;, Ang II &#x304C;&#x8A98;&#x8D77;&#x3055;&#x308C;&#x307E;&#x3059;&#x3002;&#x7D50;&#x8AD6;&#x3068;&#x3057;&#x3066;&#x3001;ATRQ&beta;-001 &#x30EF;&#x30AF;&#x30C1;&#x30F3; Ang II &#x8A98;&#x8D77;&#x9AD8;&#x8840;&#x5727;&#x30DE;&#x30A6;&#x30B9;&#x3068;&#x81EA;&#x767A;&#x7684;&#x306B;&#x6E1B;&#x5C11;&#x306E;&#x5727;&#x529B;&#x5FDC;&#x7B54;&#x3068; Ang II &#x306B;&#x3088;&#x3063;&#x3066;&#x958B;&#x59CB;&#x3055;&#x308C;&#x305F;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x963B;&#x5BB3;&#x3092;&#x901A;&#x3057;&#x3066;&#x52B9;&#x679C;&#x7684;&#x306B;&#x9AD8;&#x8840;&#x5727;&#x30E9;&#x30C3;&#x30C8;&#x306E;&#x8840;&#x5727;&#x3092;&#x6E1B;&#x5C11;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;ATRQ&beta; 001 &#x30EF;&#x30AF;&#x30C1;&#x30F3;&#x5C0F;&#x8AAC;&#x3068;&#x539F;&#x767A;&#x6027;&#x9AD8;&#x8840;&#x5727;&#x306E;&#x6CBB;&#x7642;&#x306E;&#x305F;&#x3081;&#x306E;&#x6709;&#x671B;&#x306A;&#x65B9;&#x6CD5;&#x3092;&#x63D0;&#x4F9B;&#x3059;&#x308B;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;

&#x52B9;&#x679C;&#x3068;&#x30A2;&#x30F3;&#x30B8;&#x30AA;&#x30C6;&#x30F3;&#x30B7;&#x30F3; II &#x53D7;&#x5BB9;&#x4F53;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x6CBB;&#x7642;&#x7684;&#x30EF;&#x30AF;&#x30C1;&#x30F3;&#x306E;&#x5B89;&#x5168;&#x6027;&#x306E;&#x9AD8;&#x8840;&#x5727;&#x30E2;&#x30C7;&#x30EB;&#x52D5;&#x7269; 1 &#x3092;&#x5165;&#x529B;&#x3057;&#x307E;&#x3059;&#x3002;

&#xAE30;&#xBCF8; &#xACE0;&#xD608;&#xC555;&#xC740; &#xB192;&#xC740; &#xC0AC;&#xB9DD;&#xB960;&#xACFC; &#xB9CC;&#xC131; &#xC9C8;&#xD658; &#xBC0F; &#xC81C;&#xC5B4; &#xD608;&#xC555;&#xC758; &#xC18D;&#xB3C4; &#xC9C0;&#xAE08;&#xAE4C;&#xC9C0; &#xB9CC;&#xC871; &#xC2A4;&#xB7EC;&#xC6B4;, &#xC804;&#xC138;&#xACC4;. &#xC608;&#xBC29; &#xC811;&#xC885; &#xC900;&#xC218;&#xC5D0;&#xC11C; &#xAC1C;&#xC120; &#xD558; &#xACE0; &#xACE0;&#xD608;&#xC555;&#xC758; &#xCE58;&#xB8CC;&#xB97C; &#xC704;&#xD574; &#xC720;&#xB9DD;&#xD55C; &#xC811;&#xADFC;&#xC744; &#xC81C;&#xACF5;&#xD569;&#xB2C8;&#xB2E4;. &#xC5EC;&#xAE30;, ATRQ&beta;-001 &#xBC31;&#xC2E0;, &#xD3A9; &#xD2F0; &#xB4DC; (ATR-001)&#xC5D0;&#xC11C; &#xD30C;&#xC0DD; &#xB41C; &#xC778;&#xAC04; angiotensin II (&#xC911;&#xC559; II) &#xC218;&#xC6A9; &#xCCB4; &#xD0C0;&#xC785;-1 Q&beta; &#xBC15;&#xD14C;&#xB9AC;&#xC624;&#xD30C;&#xC9C0; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xAC19;&#xC740; &#xC785;&#xC790;&#xC640; &#xD65C;&#xC6A9;, &#xAC1C;&#xBC1C; &#xD558; &#xACE0; &#xACE0;&#xD608;&#xC555;&#xC758; &#xB3D9;&#xBB3C; &#xBAA8;&#xB378;&#xC5D0;&#xC11C; &#xD3C9;&#xAC00;. ATRQ&beta;-001 &#xBC31;&#xC2E0; &#xD06C;&#xAC8C; &#xC911;&#xC559; II &#xC720;&#xBC1C; &#xACE0;&#xD608;&#xC555; &#xC950;&#xC758; &#xD608;&#xC555;&#xC744; &#xAC10;&#xC18C; 35 mm Hg (143&plusmn;4 178&plusmn;6 mm Hg; &#xB300; P = 0.005)&#xACFC; &#xC800;&#xC808;&#xB85C; &#xACE0;&#xD608;&#xC555; &#xC950;&#xC758; &#xCD5C;&#xB300; 19 mm Hg (173&plusmn;2 192&plusmn;3 mm Hg; &#xB300; P = 0.003) &#xCDE8;&#xC57D; &#xD55C; &#xACE0;&#xD608;&#xC555; &#xB300;&#xC0C1; &#xC7A5;&#xAE30;&#xC758; &#xAC1C;&#xC7A5; &#xC218; &#xC5C6;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC21C;&#xD658;&#xC758; &#xBD84;&#xBA85; &#xD55C; &#xD53C;&#xB4DC;&#xBC31; &#xD65C;&#xC131;&#xD654; &#xC5C6;&#xC74C; &#xB610;&#xB294; &#xB85C;&#xCEEC; renin angiotensin &#xC2DC;&#xC2A4;&#xD15C; &#xAD00;&#xCC30; &#xB418;&#xC5C8;&#xB2E4;. &#xB610;&#xD55C;, &#xC911;&#xC694; &#xD55C; &#xBA74;&#xC5ED; &#xC911;&#xC7AC; &#xC190;&#xC0C1; &#xC608;&#xBC29; &#xC811;&#xC885;&#xB41C; &#xACE0;&#xD608;&#xC555; &#xBC0F; nonhypertensive &#xB3D9;&#xBB3C;&#xC5D0;&#xC11C; &#xBC1C;&#xACAC; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC548;&#xD2F0;-ATR-001 &#xD56D; &#xCCB4;&#xC758; &#xBC18;&#xAC10;&#xAE30;&#xB294; &#xAE30;&#xC874; &#xD654;&#xD559; &#xC57D;&#xBB3C;&#xC744; &#xB2A5;&#xAC00; &#xD558;&#xB294; 14.4 &#xC77C; &#xC774;&#xC5C8;&#xB2E4;. &#xC2DC;&#xD5D8;&#xAD00;&#xC5D0;&#xC11C; &#xC548;&#xD2F0;-ATR-001 &#xD56D; &#xCCB4; &#xD2B9;&#xD788; &#xC911;&#xC559; II &#xC218;&#xC6A9; &#xCCB4; &#xD0C0;&#xC785;-1&#xC5D0; &#xBC14;&#xC778;&#xB529;&#xB41C; &#xBC0F; &#xC800;&#xD574; &#xB2E8;&#xBC31;&#xC9C8; &#xD0A4; &#xB2C8; &#xC544; &#xC81C; C &alpha; &#xC804;, &#xC778; &#xC0B0;&#xD654; &#xC138;&#xD3EC; &#xC678; &#xC2E0;&#xD638; &#xADDC;&#xC81C; &#xB2C8; 1/2 (72% &#xAC10;&#xC18C;;&#xB97C; &#xD3EC;&#xD568; &#xD558;&#xB294; Ca(2+) &#xC885;&#xC18D; &#xC2E0;&#xD638; &#xC804;&#xB2EC; &#xC774;&#xBCA4;&#xD2B8; P = 0.013), &#xADF8;&#xB9AC;&#xACE0; &#xC138;&#xD3EC;&#xB0B4; ca(2+)&#xC758; &#xACE0;&#xB3C4; (68% &#xAC10;&#xC18C;; P = 0.017) &#xC911;&#xC559; II &#xBC14;&#xC778;&#xB529; &#xC218;&#xC6A9; &#xCCB4;&#xB97C; &#xC5B5;&#xC81C; &#xD558;&#xC9C0; &#xC54A;&#xACE0; &#xC911;&#xC559; II &#xC720;&#xB3C4;. &#xB05D;&#xC73C;&#xB85C;, ATRQ&beta;-001 &#xBC31;&#xC2E0; &#xC911;&#xC559; II &#xC720;&#xBC1C; &#xACE0;&#xD608;&#xC555; &#xC950; &#xB4E4;&#xACFC; &#xC790;&#xBC1C;&#xC801;&#xC73C;&#xB85C; &#xC555;&#xB825; &#xC751;&#xB2F5; &#xAC10;&#xC18C; &#xBC0F; &#xC911;&#xC559; II&#xC5D0; &#xC758;&#xD574; &#xC2DC;&#xC791; &#xC2E0;&#xD638; &#xC804;&#xB2EC; &#xC5B5;&#xC81C;&#xB97C; &#xD1B5;&#xD574; &#xD6A8;&#xACFC;&#xC801;&#xC73C;&#xB85C; &#xACE0;&#xD608;&#xC555; &#xC950;&#xC758; &#xD608;&#xC555;&#xC744; &#xAC10;&#xC18C;. &#xB530;&#xB77C;&#xC11C;, ATRQ&beta;-001 &#xBC31;&#xC2E0; &#xC18C;&#xC124;&#xACFC; &#xAE30;&#xBCF8; &#xACE0;&#xD608;&#xC555; &#xCE58;&#xB8CC;&#xB97C; &#xC704;&#xD55C; &#xC720;&#xB9DD;&#xD55C; &#xBA54;&#xC11C;&#xB4DC;&#xB97C; &#xC81C;&#xACF5;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;.

&#xD6A8;&#xC728;&#xC131;&#xACFC; Angiotensin II &#xC218;&#xC6A9; &#xCCB4; &#xC720;&#xD615; 1 &#xACE0;&#xD608;&#xC555; &#xB3D9;&#xBB3C;&#xC5D0; &#xB300; &#xD55C; &#xCE58;&#xB8CC; &#xBC31;&#xC2E0;&#xC758; &#xC548;&#xC804;&#xC131;.

Hipertensi&oacute;n primaria es una enfermedad cr&oacute;nica con alta morbilidad, y la tasa de la presi&oacute;n arterial controlada est&aacute; lejos de satisfactorio, en todo el mundo. Vacunaci&oacute;n proporciona un enfoque prometedor para el tratamiento de la hipertensi&oacute;n y mejora en el cumplimiento. Aqu&iacute;, la vacuna de ATRQ&beta;-001, un p&eacute;ptido (ATR-001) deriva humana de la angiotensina II (Ang II) receptor tipo 1 conjugado con part&iacute;culas de tipo virus bacteri&oacute;fago Q&beta;, fue desarrollado y evaluado en modelos animales de hipertensi&oacute;n. La vacuna de ATRQ&beta;-001 redujo significativamente la presi&oacute;n de la sangre de ratones hipertensos de Ang II-inducida hasta 35 mm Hg (143&plusmn;4 versus 178&plusmn;6 mm Hg; P = 0,005) y que de manera espont&aacute;nea ratas hipertensas hasta 19 mm Hg (173&plusmn;2 versus 192&plusmn;3 mm Hg; P = 0, 003) y prevenir la remodelaci&oacute;n de &oacute;rganos vulnerables hipertensiva. Ninguna activaci&oacute;n de regeneraci&oacute;n evidente de circulaci&oacute;n o sistema renina-angiotensina local observ&oacute;. Adem&aacute;s, ning&uacute;n da&ntilde;o significativo inmune-mediada fue detectado en animales vacunados de hipertensos y nonhypertensive. La vida media del anticuerpo anti-ATR-001 fue 14,4 d&iacute;as, la de f&aacute;rmacos qu&iacute;micos existentes superando a. In vitro, el anticuerpo anti-ATR-001 espec&iacute;ficamente destinada a Ang II receptor tipo 1 e inhibida eventos de transducci&oacute;n de se&ntilde;al de Ca(2+)-dependiente, incluyendo desplazamiento de prote&iacute;na quinasa C-&alpha;, fosforilaci&oacute;n de la quinasa regulada por se&ntilde;al extracelular 1/2 (disminuci&oacute;n del 72%; P = 0.013) y la elevaci&oacute;n de CA intracelular (disminuci&oacute;n del 68%; P = 0,017) inducida por la Ang II, pero sin inhibir la Uni&oacute;n de Ang II al receptor. En conclusi&oacute;n, la vacuna de ATRQ&beta;-001 disminuy&oacute; la presi&oacute;n de la sangre de ratones hipertensos de Ang II-inducida y espont&aacute;neamente ratas hipertensas efectivamente a trav&eacute;s de la disminuci&oacute;n de la respuesta de la presi&oacute;n e inhibiendo la transducci&oacute;n de la se&ntilde;al iniciada por Ang II. As&iacute;, la vacuna de ATRQ&beta;-001 puede proporcionar una novela y un m&eacute;todo prometedor para el tratamiento de la hipertensi&oacute;n primaria.

Eficacia y seguridad de una vacuna terap&eacute;utica contra la angiotensina II Receptor tipo 1 de animales hipertensos.

We generated thymic stromal lymphopoietin R-chain deficient apolipoprotein E-double knockout (ApoE-TSLPR DKO) mice to directly explore the role of thymic stromal lymphopoietin (TSLP) in atherogenesis.

TSLPR deficiency attenuates atherosclerotic lesion development associated with the inhibition of TH17 cells and the promotion of regulator T cells in ApoE-deficient mice.

The pathogenesis of insulin resistance involves dysregulated gene expression and function in multiple cell types, including endothelial cells (ECs). Post-transcriptional mechanisms such as microRNA-mediated regulation of gene expression could affect insulin action by modulating EC function.

MicroRNA-181b Improves Glucose Homeostasis and Insulin Sensitivity by Regulating Endothelial Function in White Adipose Tissue.

Thrombogenic and inflammatory mediators, such as thrombin, induce NF-κB-mediated endothelial cell (EC) activation and dysfunction, which contribute to pathogenesis of arterial thrombosis. The role of anti-inflammatory microRNA-181b (miR-181b) on thrombosis remains unknown. Our previous study demonstrated that miR-181b inhibits downstream NF-κB signaling in response to TNF-α. Here, we demonstrate that miR-181b uniquely inhibits upstream NF-κB signaling in response to thrombin. Overexpression of miR-181b inhibited thrombin-induced activation of NF-κB signaling, demonstrated by reduction of phospho-IKK-β, -IκB-α, and p65 nuclear translocation in ECs. MiR-181b also reduced expression of NF-κB target genes VCAM-1, intercellular adhesion molecule-1, E-selectin, and tissue factor. Mechanistically, miR-181b targets caspase recruitment domain family member 10 (Card10), an adaptor protein that participates in activation of the IKK complex in response to signals transduced from protease-activated receptor-1. miR-181b reduced expression of Card10 mRNA and protein, but not protease-activated receptor-1. 3'-Untranslated region reporter assays, argonaute-2 microribonucleoprotein immunoprecipitation studies, and Card10 rescue studies revealed that Card10 is a bona fide direct miR-181b target. Small interfering RNA-mediated knockdown of Card10 expression phenocopied effects of miR-181b on NF-κB signaling and targets. Card10 deficiency did not affect TNF-α-induced activation of NF-κB signaling, which suggested stimulus-specific regulation of NF-κB signaling and endothelial responses by miR-181b in ECs. Finally, in response to photochemical injury-induced arterial thrombosis, systemic delivery of miR-181b reduced thrombus formation by 73% in carotid arteries and prolonged time to occlusion by 1.6-fold, effects recapitulated by Card10 small interfering RNA. These data demonstrate that miR-181b and Card10 are important regulators of thrombin-induced EC activation and arterial thrombosis. These studies highlight the relevance of microRNA-dependent targets in response to ligand-specific signaling in ECs.-Lin, J., He, S., Sun, X., Franck, G., Deng, Y., Yang, D., Haemmig, S., Wara, A. K. M., Icli, B., Li, D., Feinberg, M. W. MicroRNA-181b inhibits thrombin-mediated endothelial activation and arterial thrombosis by targeting caspase recruitment domain family member 10.

MicroRNA-181b inhibits thrombin-mediated endothelial activation and arterial thrombosis by targeting caspase recruitment domain family member 10.

Recently, studies have shown that interleukin-37 (IL-37) is involved in atherosclerosis-related diseases. However, the regulatory mechanisms of IL-37 in atherosclerosis remain unknown. This study aims to determine the role of IL-37 in atherosclerosis and to investigate the underlying mechanisms involved.

Transgenic Overexpression of IL-37 Protects Against Atherosclerosis and Strengthens Plaque Stability.

Pulmonary arterial hypertension (PAH) is a chronic fatal disease. The treatment of PAH is less than ideal and the control is far from satisfactory worldwide. Vaccination provides a promising approach for treatment of PAH.

Immunotherapy of Endothelin-1 Receptor Type A for Pulmonary Arterial Hypertension.

Regulatory T cells (Tregs) have been shown to attenuate the development and progression of atherosclerosis; however, the exact mechanism is still unclear. In our study, Tregs were adoptively transferred into ApoE mice, and type 2 innate lymphoid cells (ILC2s) were expanded by the IL-2/Jes6-1 complex or depleted by anti-CD90.2 mAb in ApoERag1 mice to study their effects on atherosclerosis. Then, Tregs were cocultured with ILC2s in vitro to analyze ILC2s number and IL-13 production. In vivo, ApoERag1 mice were treated with activated Tregs with or without anti-CD90.2 mAb to explore whether Tregs reduced atherosclerosis through ILC2s. Finally, neutralizing antibodies and Transwell assay were used to investigate how Tregs regulate ILC2s. Our results show that both Tregs and ILC2s reduce atherosclerosis lesions and macrophage infiltration. Moreover, Tregs effectively expanded the number of ILC2s and increased their production of IL-13 in vivo and in vitro. Furthermore, the reductions in plaque size and macrophage infiltration by Tregs were partly reversed by anti-CD90.2 mAb. Mechanistically, our data reveal that IL-10, TGF-β and cell-cell contacts are required for Tregs-ILC2s regulation. These results show that Tregs may play a partial protective role against atherosclerosis by expanding the number of ILC2s and consequently increasing IL-13 production.

Type 2 innate lymphoid cells regulation by regulatory T cells attenuates atherosclerosis.

Bortezomib is a classical proteasome inhibitor and previous researches have reported its roles of anti-oxidation and anti-inflammatory functions in various diseases. However, the role of Bortezomib in myocardial ischemia reperfusion injury (MIRI) is unclear. Thus, our research seeks to reveal the protective effects of Bortezomib pretreatment in the mice model of MIRI. First, by the optimization of Bortezomib concentration and pretreatment timepoints, we found that 0.5 mg/kg Bortezomib pretreatment 2 h before MIRI significantly attenuated pathological damage and neutrophil infiltration. Then we found that pretreatment with Bortezomib obviously increased myocardial systolic function ((left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS)) and decreased infarct size, as well as serum Troponin T levels. Meanwhile, Bortezomib pretreatment also remarkably augmented oxidative stress related protein levels of Superoxide dismutase [Cu-Zn] (SOD1), Catalase (CAT) and Glutathione (GSH), while reactive oxygen species (ROS) contents and Malonaldehyde (MDA) protein level were significantly reduced. Mechanistically, Bortezomib pretreatment significantly promoted nuclear translocation of transcriptional factor nuclear factor erythroid 2-related factor 2(Nrf2) and Heme Oxygenase 1(HO-1) expression. Interestingly, co-treatment with ML-385, a new type and selective Nrf2 inhibitor, counteracted antioxidative effects induced by Bortezomib pretreatment. In conclusion, Bortezomib pretreatment mitigates MIRI by inhibiting oxidative damage which is regulated by Nrf2/HO-1 signaling pathway.

Bortezomib alleviates myocardial ischemia reperfusion injury via enhancing of Nrf2/HO-1 signaling pathway.

Myocardial infarction results from obstruction of a coronary artery that causes insufficient blood supply to the myocardium and leads to ischemic necrosis. It is one of the most common diseases threatening human health and is characterized by high morbidity and mortality. Atherosclerosis is the pathological basis of myocardial infarction, and its pathogenesis has not been fully elucidated. Innate lymphoid cells (ILCs) are an important part of the human immune system and participate in many processes, including inflammation, metabolism and tissue remodeling, and play an important role in atherosclerosis. However, their specific roles in myocardial infarction are unclear. This review describes the current understanding of the relationship between innate lymphoid cells and myocardial infarction during the acute phase of myocardial infarction, myocardial ischemia-reperfusion injury, and heart repair and regeneration following myocardial infarction. We suggest that this review may provide new potential intervention targets and ideas for treatment and prevention of myocardial infarction.

Jibin Lin

Department of Cardiology,
Union Hospital,
Tongji Medical College,
Department of Cardiology, Union Hospital, Tongji Medical College

Huazhong University of Science and Technology

Induction of Myocardial Infarction and Myocardial Ischemia-Reperfusion Injury in Mice

Jibin Lin

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Cardiology,Union Hospital,Tongji Medical College,Department of Cardiology, Union Hospital, Tongji Medical College

Huazhong University of Science and Technology

Induction of Myocardial Infarction and Myocardial Ischemia-Reperfusion Injury in Mice

Department of Cardiology,
Union Hospital,
Tongji Medical College,
Department of Cardiology, Union Hospital, Tongji Medical College