interleukin-8 and trimethyloxamine

Myocardial infarction (MI) is a common cause of chronic heart failure (HF). Increasing evidence has revealed that trimethylamine N‑oxide (TMAO), a gut‑microbiota‑derived metabolite, contributes to the pathogenesis of cardiovascular disease by promoting inflammation. Elevated levels of circulating TMAO have been reported in patients following MI and were associated with unfavorable outcomes. The present study examined whether reductions in circulating TMAO could attenuate the progression of HF in rats following MI. Sprague‑Dawley rats underwent coronary ligation to induce MI or a sham operation. Echocardiography confirmed MI and cardiac dysfunction one day following coronary ligation. MI and sham rats were then treated with either vehicle (tap water) or 1.0% 3,3‑dimethyl‑1‑butanol (DMB, a trimethylamine formation inhibitor) in tap water, for 8 weeks. At the end of the experiment, TMAO plasma levels were markedly elevated in vehicle‑treated MI rats compared with vehicle‑treated sham rats; however, TMAO plasma levels were reduced in DMB‑treated MI rats compared with vehicle‑treated MI rats. Both MI groups exhibited cardiac hypertrophy, lung congestion, left ventricular remodeling and impaired cardiac function, according to the results of anatomical analysis, echocardiography and left ventricular hemodynamics; however, these manifestations of MI‑induced HF were significantly improved in DMB‑treated MI rats compared with vehicle‑treated MI rats. The plasma levels of the chemokine interleukin (IL)‑8, and cardiac expression of IL‑8 and its receptors were significantly increased in vehicle‑treated MI rats compared with vehicle‑treated sham rats; however, these were normalized in DMB‑treated MI rats. In addition, elevated TMAO plasma level was positively correlated with increased IL‑8 plasma level in MI groups. Notably, DMB treatment of sham rats also reduced plasma TMAO, but did not alter other parameters. These results indicated that reducing circulating TMAO may ameliorate the development of chronic HF following MI in rats, potentially by inhibiting IL‑8 secretion. The results from the present study suggested that inhibition of TMAO synthesis may be considered as a novel therapeutic approach for the prevention and treatment of patients with chronic MI‑induced HF.

Topics: Animals; Gastrointestinal Microbiome; Heart Failure; Hexanols; Interleukin-8; Male; Methylamines; Myocardial Infarction; Rats; Rats, Sprague-Dawley

We have used trimethylamine N-oxide (TMAO), a protecting osmolyte, to dissect the complex thermodynamic linkages involved in the interaction between the chemokine interleukin-8 (IL-8) and the N-domain of its receptor CXCR1. Our results show that TMAO induces folding in the CXCR1 receptor N-domain and that the N-domain upon folding binds ligand with higher affinity. This represents, to our knowledge, the smallest domain that has been shown to be folded in osmolyte. Using the phase diagram method to analyze this thermodynamic relationship graphically, we also observe that TMAO favors ligand dimerization and that the dimeric ligand binds the receptor domain with lower affinity. We have thus been able to dissect coupling among three distinct processes, receptor domain folding, ligand dimerization, and ligand-receptor domain binding in this chemokine-receptor system. We also observe that the affinity of the related chemokine, melanoma growth stimulatory activity (MGSA), increases concurrent with N-domain folding similar to IL-8 but shows more profound differences on ligand dimerization. These studies establish a novel and innovative use of osmolytes to dissect linkages among different processes and exploit the phase diagram as a tool to graphically represent and dissect complex thermodynamic relationships in biological systems. On the basis of our observations and earlier work, we discuss the relevance of ligand dimerization in chemokine regulation.

Topics: Chemokine CXCL1; Chemokines, CXC; Dimerization; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-8; Methylamines; Protein Binding; Protein Folding; Protein Structure, Tertiary; Receptors, Interleukin-8A; Thermodynamics