Role of NOD1 in atrial myopathy associated with heart failure

Resumen

Heart failure (HF) is a complex syndrome that constitutes one of the leading causes of cardiovascular death worldwide. The mechanisms involved in HF-atrial myopathy are complex and poorly understood. In this regard, novel studies emerged focusing on the role of the inflammatory response and the innate immune system as key factors in the development of atrial damage in HF. Accordingly, innate immune receptors such as nucleotide oligomerization domain (NOD)-like receptors (NLRs) are being extensively studied in atrial myopathy. However, the role of NOD-containing protein 1 (NOD1) receptors in the progression of atrial damage during HF was completely unknown. Therefore, the main objective of the present Doctoral Thesis is to analyse the role of NOD1 receptor in atrial remodelling associated with HF. First, we analysed the expression of NOD1 in atrial myocardium from patients with and without HF that undergone valve surgery. Our results showed increased protein levels of NOD1, as well as in inflammatory mediators derived from its activation in atria from HF vs. non-failing patients. The incidence of atrial fibrillation (AF) did not impair the increased expression of this receptor in the failing atria. In addition, we observed that this increase in NOD1 expression correlated with atrial structural and functional impairment. Data from human samples were corroborated in two swine models of atrial damage, one of ischaemic HF (LAI) and the other of atrial damage induced by pressure overload (AoB). In both cases NOD1 expression was significantly higher in the failing atrium compared to control tissue, showing a significant correlation between NOD1 protein levels and atrial structural damage and dysfunction. To better understand the role of NOD1 in this context, atrial remodelling was evaluated in a mouse model of HF induced by pressure overload by transverse aortic constriction (Tac) in wild-type (Wt, expressing NOD1) and Nod knockout (Nod1-/-) mice. Our results showed that the genetic deletion of NOD1 prevented atrial dysfunction and structural damage in Tac animals, as well as the dysregulation of atrial intracellular Ca2+ handling. Mechanistically, these effects were mediated by Ca2+/calmodulin-dependent protein kinase II (CaMKII). Likewise, administration of a selective NOD1 agonist to Wt mice resulted in atrial structural remodelling together with a dysregulation of intracellular Ca2+ handling, also mediated by CaMKII. On the other hand, we found increased levels of S100A8/A9 alarmins in serum samples from patients and atrial tissue from failing individuals, pigs, and mice, as well as a correlation between atrial levels of these alarmins and NOD1 expression. Finally, in vitro experiments in a human cardiac cell line proved that S100A8/A9 can induce the activation of NOD1 signalling pathway mediated by its specific adapter, the receptor-interacting protein 2 (RIP2). The present Doctoral Thesis demonstrates the participation of NOD1 in the development of atrial myopathy in the failing heart, unravelling new mechanisms involved in HF pathophysiology.