Deficiency of Nucleotide-binding oligomerization domain-containing proteins (NOD) 1 and 2 reduces atherosclerosis

Abstract

Atherosclerosis is crucially fueled by inflammatory pathways including pattern recognition receptor (PRR)-related signaling of the innate immune system. Currently, the impact of the cytoplasmic PRRs nucleotide-binding oligomerization domaincontaining protein (NOD) 1 and 2 is incompletely characterized. We, therefore, generated Nod1/Nod2 double knockout mice on a low-density lipoprotein receptor (Ldlr)-deficient background (= Ldlr −/− Nod1/2 −/−) which were subsequently analyzed regarding experimental atherosclerosis, lipid metabolism, insulin resistance and gut microbiota composition. Compared to Ldlr −/− mice, Ldlr −/− Nod1/2 −/− mice showed reduced plasma lipids and increased hepatic expression of the scavenger receptor LDL receptor-related protein 1 after feeding a high-fat diet for 12 weeks. Furthermore, intestinal cholesterol and its bacterial degradation product coprostanol were elevated in Ldlr −/− Nod1/2 −/− mice, correlating with the increased abundance of Eubacterium coprostanoligenes as assessed by 3rd generation sequencing of the gut microbiota. Atherosclerotic plaques of Ldlr −/− Nod1/2 −/− mice exhibited less lipid deposition and macrophage accumulation. Moreover, macrophages from Ldlr −/− Nod1/2 −/− mice showed higher expression of the cholesterol efflux transporters Abca1 and Abcg1 and accordingly reduced foam cell formation. Deficiency of Nod1 and Nod2 led to reduced plaque lipid deposition and inflammatory cell infiltration in atherosclerotic plaques. This might be explained by diminished plasma lipid levels and foam cell formation due to altered expression of key regulators of the hepatic cholesterol pathway as well as differential intestinal cholesterol metabolism and microbiota composition.

Deletion or Inhibition of NOD1 Favors Plaque Stability and Attenuates Atherothrombosis in Advanced Atherogenesis

“…Therefore, our findings demonstrating a direct link between NOD1 and plaque vulnerability in Apoe −/− mice may be helpful to the clinical practice in terms of the events that precede plaque rupture during atherothrombosis, such as NC formation, the cell-death in the lesion area or the composition of the fibrotic tissue. Moreover, a recent work combining Nod1 and Nod2 deficiency under the Ldlr −/− background shows similar results to those reported in this work [ 28 ]; however, in our animal model, whereas NOD1 was highly upregulated under HFD regime, NOD2 levels remained unchanged ( Figure S9 ) stressing the relevance of NOD1 in the context of atherosclerosis.…”

RETRACTED: Molecular Perspectives of Mitophagy in Myocardial Stress: Pathophysiology and Therapeutic Targets

“…Under normoxic conditions, BCL2L1 binds to PGAM5 and inhibits its phosphatase activity, thus preventing FUNDC1 dephosphorylation and inhibiting mitophagy. However, following hypoxia or FCCP treatment, BCL2L1 is degraded, PGAM5 is activated, and FUNDC1 is dephosphorylated at Ser13, thus inducing mitophagy ( Ma et al, 2020a ; Vlacil et al, 2020 ). Loss- and gain-of-function assays indicated that the BCL2L1 level determines the extent of PGAM5-induced FUNDC1 dephosphorylation and mitophagy ( Ma et al, 2020a ).…”

Pattern recognition receptors in health and diseases

“… 409 In addition to TLRs, the lack of NOD1 and NOD2 can lead to lipid deposition of atherosclerotic plaques and the reduction of inflammatory cell infiltration, so it has been identified as pre-disease factors. 410 …”