Role of NOD1 in Heart Failure Progression via Regulation of Ca²⁺ Handling

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• 作者：Almudena Val-Blasco ; BsC^a ; Marí ; a Jose G.M. Piedras ; PhD^b ; Gema Ruiz-Hurtado ; PhD^c ; Natalia Suarez ; PhD^d ; Patricia Prieto ; PhD^e ; Silvia Gonzalez-Ramos ; BsC^e ; Nieves Gó ; mez-Hurtado ; PhD^f ; Carmen Delgado ; PhD^e ; ^f ; Laetitia Pereira ; PhD^g ; Gemma Benito ; BsC^a ; Carlos Zaragoza ; PhD^b ; Nieves Domenech ; PhD^h ; Marí ; a Generosa Crespo-Leiro ; MD ; PhD^d ; Daniel Vasquez-Echeverri ; PhD^d ; Gabriel Nuñ ; ez ; MD ; PhDⁱ ; Eduardo Lopez-Collazo ; PhD^a ; ^j ; Lisardo Boscá ; PhD^e ; ^{lbosca@iib.uam.es} ; Marí ; a Ferná ; ndez-Velasco ; PhD^a ; ^{mvelasco@iib.uam.es} ; ^{maria.fernandez@idipaz.es}
• 关键词：calcium ; cardiac arrhythmia ; cardiac dysfunction ; innate immune system ; myocardial infarction ; ryanodine receptor
• 刊名：Journal of the American College of Cardiology
• 出版年：2017
• 出版时间：31 January 2017
• 年：2017
• 卷：69
• 期：4
• 页码：423-433
• 全文大小：3211 K
• 卷排序：69

文摘

Heart failure (HF) is a complex syndrome associated with a maladaptive innate immune system response that leads to deleterious cardiac remodeling. However, the underlying mechanisms of this syndrome are poorly understood. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a newly recognized innate immune sensor involved in cardiovascular diseases.ObjectivesThis study evaluated the role of NOD1 in HF progression.MethodsNOD1 was examined in human failing myocardium and in a post-myocardial infarction (PMI) HF model evaluated in wild-type (wt-PMI) and Nod1–/– mice (Nod1–/–-PMI).ResultsThe NOD1 pathway was up-regulated in human and murine failing myocardia. Compared with wt-PMI, hearts from Nod1–/–-PMI mice had better cardiac function and attenuated structural remodeling. Ameliorated cardiac function in Nod1–/–-PMI mice was associated with prevention of Ca2+ dynamic impairment linked to HF, including smaller and longer intracellular Ca2+ concentration transients and a lesser sarcoplasmic reticulum Ca2+ load due to a down-regulation of the sarcoplasmic reticulum Ca2+-adenosine triphosphatase pump and by augmented levels of the Na+/Ca2+ exchanger. Increased diastolic Ca2+ release in wt-PMI cardiomyocytes was related to hyperphosphorylation of ryanodine receptors, which was blunted in Nod1–/–-PMI cardiomyocytes. Pharmacological blockade of NOD1 also prevented Ca2+ mishandling in wt-PMI mice. Nod1–/–-PMI mice showed significantly fewer ventricular arrhythmias and lower mortality after isoproterenol administration. These effects were associated with lower aberrant systolic Ca2+ release and with a prevention of the hyperphosphorylation of ryanodine receptors under isoproterenol administration in Nod1–/–-PMI mice.ConclusionsNOD1 modulated intracellular Ca2+ mishandling in HF, emerging as a new target for HF therapy.