Effects of in vivo treatment with interleukins 1β and 6 on rat mesenteric vascular bed reactivity

Cherng

Journal of Hypertension

et al. 2010

In addition to decreasing Akt phosphorylation, the results of this study demonstrate, for the first time, the molecular mechanism underlying the effect of IL-6 to decrease the nitric oxide bioavailability by increasing the half-life and, therefore, the protein levels of caveolin-1. The increased caveolin-1 proteins bind more eNOS and consequently decrease eNOS activation by reducing the Ser1177 phosphorylation.

Section: Relationship Between Interleukin-6 and Endothelial Nitric Oxmentioning

confidence: 97%

Interleukin-6 inhibits endothelial nitric oxide synthase activation and increases endothelial nitric oxide synthase binding to stabilized caveolin-1 in human vascular endothelial cells

Cherng

Journal of Hypertension

et al. 2010

“…24 Conversely, they can also enhance vasoconstrictor responses to other agents because of the loss of endothelial integrity to blunt these responses. 24,25 This might explain why the relative contraction to phenylephrine was significantly increased in MC1R To extend the findings in MC1R e/e mice to a clinical perspective, we explored the association of human MC1-R variants to early markers of atherosclerotic changes. The vascular phenotype of MC1R e/e mice was highly concordant with the data from young adults.…”

Section: Discussionmentioning

confidence: 99%

Deficiency in Melanocortin 1 Receptor Signaling Predisposes to Vascular Endothelial Dysfunction and Increased Arterial Stiffness in Mice and Humans

Rinne

Ahola‐Olli

Nuutinen

et al. 2015

ATVB

Objective— The melanocortin 1 receptor (MC1-R) is expressed by vascular endothelial cells and shown to enhance nitric oxide (NO) availability and vasodilator function on pharmacological stimulation. However, the physiological role of MC1-R in the endothelium and its contribution to vascular homeostasis remain unresolved. We investigated whether a lack of functional MC1-R signaling carries a phenotype with predisposition to vascular abnormalities. Approach and Results— Recessive yellow mice (MC1R e/e ), deficient in MC1-R signaling, and their wild-type littermates were studied for morphology and functional characteristics of the aorta. MC1R e/e mice showed increased collagen deposition and arterial stiffness accompanied by an elevation in pulse pressure. Contractile capacity and NO-dependent vasodilatation were impaired in the aorta of MC1R e/e mice supported by findings of decreased NO availability. These mice also displayed elevated levels of systemic and local cytokines. Exposing the mice to high-sodium diet or acute endotoxemia revealed increased susceptibility to inflammation-driven vascular dysfunction. Finally, we investigated whether a similar phenotype can be found in healthy human subjects carrying variant MC1-R alleles known to attenuate receptor function. In a longitudinal analysis of 2001 subjects with genotype and ultrasound data (The Cardiovascular Risk in Young Finns Study), weak MC1-R function was associated with lower flow-mediated dilatation response of the brachial artery and increased carotid artery stiffness. Conclusions— The present study demonstrates that deficiency in MC1-R signaling is associated with increased arterial stiffness and impairment in endothelium-dependent vasodilatation, suggesting a physiological role for MC1-R in the regulation of arterial tone.

American Journal of Physiology-Gastrointestinal and Liver Physi

“…Mechanical effects of inflammatory mediators on colonic motility have been carefully studied and found to be primarily due to effects on neurotransmission (7,30). Other functional effects might include regulation of lymphocyte and mast cell influx to the muscularis and vasculitis of the inflamed colon (9). RANTES and IL-8 are promigratory chemokines that attract monocytes and neutrophils to sites were they are produced.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory gene expression by human colonic smooth muscle cells

Salinthone

Singer

Gerthoffer

2004

Intestinal mucosal cells and invading leukocytes produce inappropriate levels of cytokines and chemokines in human colitis. However, smooth muscle cells of the airway and vasculature also synthesize cytokines and chemokines. To determine whether human colonic myocytes can synthesize proinflammatory mediators, strips of circular smooth muscle and smooth muscle cells were isolated from human colon. Myocytes and muscle strips were stimulated with 10 ng/ml of IL-1β, TNF-α, and IFN-γ, respectively. Expression of mRNA for IL-1β, IL-6, IL-8, and cyclooxygenase-2 (COX-2) was induced within 2 h and continued to increase for 8–12 h. Regulated on activation, normal T cell-expressed and -secreted (RANTES) mRNA expression was slower, appearing at 8 h and increasing linearly through 20 h. Expression of all five mRNAs was inhibited by 0.1 μM MG-132, a proteosome inhibitor that blocks NF-κB activation. Expression of IL-1β, IL-6, IL-8, and COX-2 mRNA was reduced by 30 μM PP1, an Src family tyrosine kinase inhibitor, and by 25 μM SB-203580, a p38 MAPK inhibitor. MAPK/extracellular regulated kinase-1 inhibitor PD-98059 (25 μM) was much less effective. In conclusion, human colonic smooth muscle cells can synthesize and secrete interleukins (IL-1β and IL-6) and chemokines (IL-8 and RANTES) and upregulate expression of COX-2. Regulation of cytokine, chemokine, and COX-2 mRNA depends on multiple signaling pathways, including Src-family kinases, extracellular regulated kinase, p38 MAPKs, and NF-κB. SB-203580 was a consistent, efficacious inhibitor of inflammatory gene expression, suggesting an important role of p38 MAPK in synthetic functions of human colonic smooth muscle.