NOD1 activation in cardiac fibroblasts induces myocardial fibrosis in a murine model of type 2 diabetes

• Published in: Biochemical journal Vol. 474; no. 3; p. 399
• Main Authors: Val-Blasco, Almudena, Prieto, Patricia, Gonzalez-Ramos, Silvia, Benito, Gemma, Vallejo-Cremades, María Teresa, Pacheco, Ivette, González-Peramato, Pilar, Agra, Noelia, Terrón, Verónica, Delgado, Carmen, Martín-Sanz, Paloma, Boscá, Lisardo, Fernández-Velasco, María
• Format: Journal Article
• Language: English
• Published: England 01-02-2017
• Subjects: Animals; Blood Glucose - metabolism; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diaminopimelic Acid - analogs & derivatives; Diaminopimelic Acid - pharmacology; Endomyocardial Fibrosis - genetics; Endomyocardial Fibrosis - metabolism; Endomyocardial Fibrosis - pathology; Endomyocardial Fibrosis - prevention & control; Gene Expression Regulation; Humans; Insulin - blood; Insulin Resistance; Mice; Mice, Transgenic; Myocardium - metabolism; Myocardium - pathology; NF-kappa B - antagonists & inhibitors; NF-kappa B - genetics; NF-kappa B - metabolism; NIH 3T3 Cells; Nitriles - pharmacology; Nod1 Signaling Adaptor Protein - agonists; Nod1 Signaling Adaptor Protein - genetics; Nod1 Signaling Adaptor Protein - metabolism; Signal Transduction; Sulfones - pharmacology; Transforming Growth Factor beta - agonists; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism
• ISSN: 1470-8728
• DOI: 10.1042/BCJ20160556

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.