NOD1 activation in cardiac fibroblasts induces myocardial fibrosis in a murine model of type 2 diabetes.
Cardiac fibrosis and chronic inflammation are common complications in type 2 diabetes mellitus (T2D). Since nucleotide oligomerization-binding domain 1 (NOD1), an innate immune receptor, is involved in the pathogenesis of insulin resistance and diabetes outcomes, we sought to investigate its involvement in cardiac fibrosis. Here, we show that selective staining of cardiac fibroblasts from T2D (db/db;db) mice exhibits up-regulation and activation of the NOD1 pathway, resulting in enhanced NF-κB and TGF-β signalling. Activation of the TGF-β pathway in cardiac fibroblasts from db mice was prevented after inhibition of NF-κB with BAY-11-7082 (BAY). Moreover, fibrosis progression in db mice was also prevented by BAY treatment. Enhanced TGF-β signalling and cardiac fibrosis of db mice was dependent, at least in part, on the sequential activation of NOD1 and NF-κB since treatment of db mice with a selective NOD1 agonist induced activation of the TGF-β pathway, but co-administration of a NOD1 agonist plus BAY, or a NOD1 inhibitor prevented the NOD1-induced fibrosis. Therefore, NOD1 is involved in cardiac fibrosis associated with diabetes, and establishes a new mechanism for the development of heart fibrosis linked to T2D.
Instituto de Investigación Hospital Universitario la PAZ, IdIPAZ, Paseo de la Castellana, Madrid 28046, Spain.
Almudena
A
Val-Blasco
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC-UAM), Arturo Duperier 4, Madrid 28029, Spain.
Patricia
P
Prieto
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC-UAM), Arturo Duperier 4, Madrid 28029, Spain.
Silvia
S
Gonzalez-Ramos
Instituto de Investigación Hospital Universitario la PAZ, IdIPAZ, Paseo de la Castellana, Madrid 28046, Spain.
Gemma
G
Benito
Instituto de Investigación Hospital Universitario la PAZ, IdIPAZ, Paseo de la Castellana, Madrid 28046, Spain.
María Teresa
MT
Vallejo-Cremades
Hospital Militar de Managua, Managua, Nicaragua.
Ivette
I
Pacheco
Instituto de Investigación Hospital Universitario la PAZ, IdIPAZ, Paseo de la Castellana, Madrid 28046, Spain.
Pilar
P
González-Peramato
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC-UAM), Arturo Duperier 4, Madrid 28029, Spain.
Noelia
N
Agra
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC-UAM), Arturo Duperier 4, Madrid 28029, Spain.
Verónica
V
Terrón
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC-UAM), Arturo Duperier 4, Madrid 28029, Spain.
Carmen
C
Delgado
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC-UAM), Arturo Duperier 4, Madrid 28029, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Instituto de Salud Carlos III, Madrid 28029, Spain.
Paloma
P
Martín-Sanz
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC-UAM), Arturo Duperier 4, Madrid 28029, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Instituto de Salud Carlos III, Madrid 28029, Spain.
Lisardo
L
Boscá
Instituto de Investigación Hospital Universitario la PAZ, IdIPAZ, Paseo de la Castellana, Madrid 28046, Spain.
María
M
Fernández-Velasco
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003960:Diaminopimelic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004719:Endomyocardial Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009570:Nitriles / Q000494:pharmacology; D053474:Nod1 Signaling Adaptor Protein / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000819:agonists / Q000235:genetics / Q000378:metabolism
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D001786:Blood Glucose; D007328:Insulin; D016328:NF-kappa B; D009570:Nitriles; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D013450:Sulfones; D016212:Transforming Growth Factor beta; D003960:Diaminopimelic Acid; C034331:N(2)-(gamma-D-glutamyl)-meso-2,2'-diaminopimelic acid