The Effect of Salsalate Therapy on Endothelial Function in a Broad Range of Subjects

Nohria, Anju; Kinlay, Scott; Buck, Jackie; Redline, Whitney; Copeland‐Halperin, Robert S.; Kim, Sora; Beckman, Joshua A.

doi:10.1161/jaha.113.000609

Cited by 33 publications

(27 citation statements)

References 59 publications

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“…In contrast, no effects on flow-mediated dilation were seen in persons with T2D who received salsalate at 3.5 g/d over six months (135). It remains unknown whether these differences are due to dosage or study population, or whether the effects of short-term are not sustained, as mixed effects have been reported in additional investigations (131,136,137). To address whether salsalate can reduce progression of non-calcified coronary plaque, a timely question given the inflammatory hypothesis of atherosclerosis, 190 overweight or obese persons with established coronary heart disease taking statin therapy were randomized to salsalate (3.5 g/d) or placebo and followed by multidetector computed tomographic angiography over 30 months (138).…”

Section: Pharmacologic Approaches That Directly Target Inflammationmentioning

confidence: 98%

Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk

Goldfine¹,

Shoelson²

2017

Journal of Clinical Investigation

139

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Obesity-related sub-acute chronic inflammation has been associated with incident type 2 diabetes and atherosclerotic cardiovascular disease. Inflammation is increasingly considered to be a pathologic mediator of these commonly co-occurring diseases. A growing number of preclinical and clinical studies support the inflammatory hypothesis, but clinical trials to confirm the therapeutic potential to target inflammation to treat or prevent cardiometabolic conditions are still ongoing. There are multiple inflammatory signaling pathways. Regulation is complex, with substantial crosstalk across these multiple pathways. The activity of select pathways may be differentially regulated in different tissues. Pharmacologic approaches to diabetes management may have direct or indirect antiinflammatory effects, the latter potentially attributable to an improved metabolic state. Conversely, some antiinflammatory approaches may affect glucose metabolism and cardiovascular health. To date, clinical trials suggest that targeting one portion of the inflammatory cascade may differentially affect dysglycemia and atherothrombosis. Understanding the underlying biological processes may contribute to the development of safe and effective therapies, although a single approach may not be sufficient for optimal management of both metabolic and athrothrombotic disease states.

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Section: Pharmacologic Approaches That Directly Target Inflammationmentioning

confidence: 98%

Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk

Goldfine¹,

Shoelson²

2017

Journal of Clinical Investigation

139

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“…Second, in patients, products of cyclooxygenase (Nohria et al . ), hydrogen peroxide (H 2 O 2 ; Kang et al . , Freed et al .…”

Section: Nitric Oxidementioning

confidence: 99%

“…) or other EDH‐mediators (Nohria et al . ) may contribute to the response to increases in shear stress. Third, one should always consider the possibility that reductions in responses to shear stress or endothelium‐dependent vasodilator agents can be due to the concomitant release of endothelium‐derived vasoconstrictors (see sections and ), or to a reduced (e.g.…”

Section: Nitric Oxidementioning

confidence: 99%

Endothelial dysfunction and vascular disease - a 30th anniversary update

Vanhoutte¹,

et al. 2016

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The endothelium can evoke relaxations of the underlying vascular smooth muscle, by releasing vasodilator substances. The best-characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) which activates soluble guanylyl cyclase in the vascular smooth muscle cells, with the production of cyclic guanosine monophosphate (cGMP) initiating relaxation. The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDH-mediated responses). As regards the latter, hydrogen peroxide (H O ) now appears to play a dominant role. Endothelium-dependent relaxations involve both pertussis toxin-sensitive G (e.g. responses to α -adrenergic agonists, serotonin, and thrombin) and pertussis toxin-insensitive G (e.g. adenosine diphosphate and bradykinin) coupling proteins. New stimulators (e.g. insulin, adiponectin) of the release of EDRFs have emerged. In recent years, evidence has also accumulated, confirming that the release of NO by the endothelial cell can chronically be upregulated (e.g. by oestrogens, exercise and dietary factors) and downregulated (e.g. oxidative stress, smoking, pollution and oxidized low-density lipoproteins) and that it is reduced with ageing and in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively lose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and EDH, in particular those due to H O ), endothelial cells also can evoke contraction of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factors. Recent evidence confirms that most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells and that prostacyclin plays a key role in such responses. Endothelium-dependent contractions are exacerbated when the production of nitric oxide is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive and diabetic patients. In addition, recent data confirm that the release of endothelin-1 can contribute to endothelial dysfunction and that the peptide appears to be an important contributor to vascular dysfunction. Finally, it has become clear that nitric oxide itself, under certain conditions (e.g. hypoxia), can cause biased activation of soluble guanylyl cyclase leading to the production of cyclic inosine monophosphate (cIMP) rather than cGMP and hence causes contraction rather than relaxation of the underlying vascular smooth muscle.

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“…Large-scale clinical trials are underway to investigate whether anti-inflammatory treatment improves cardiovascular outcomes, for example, methotrexate therapy (TETHYS trial and CIRT trial) [95,96] and blockade of the cytokine IL-1β with canakinumab for the management of cardiovascular disease (CANTOS trial) [97,98]. Additionally, randomized, placebo-controlled, double-masked clinical trials of salsalate [99,100], IL1Ra [101,102] and anti-TNF-α [103] are being used to determine whether these anti-inflammatory approaches modify disease risk in type 2 diabetes and atherosclerotic cardiovascular disease.…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Endothelial Dysfunction in Type 2 Diabetes: Targeting Inflammation

Sena¹,

Carrilho²,

Seiça³

2018

Endothelial Dysfunction - Old Concepts and New Challenges

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Several experimental and clinical studies have indicated a prominent role of vascular inflammation in the development of endothelial dysfunction. In endothelial dysfunction, the endothelium loses its physiological features, decrements nitric oxide bioavailability, and shifts towards a vasoconstrictor, pro-thrombotic and pro-inflammatory state. Within arterial wall, the interplay between the pro-inflammatory and pro-oxidant milieus promotes vascular dysfunction, and perivascular adipose tissue seems to play an important role. Inflammation is now considered a key event in vascular dysfunction and the development of vascular disease associated with obesity and type 2 diabetes. This concept is supported by the fact that anti-inflammatory adipokines such as adiponectin protect endothelial function, and interventions resulting in reduced inflammation such as the administration of salicylates prevent vascular dysfunction and cardiovascular events. Thus, the aim of this review is to address the role of inflammation and its mechanisms in endothelial dysfunction associated with diabetes, describing the impact of these conditions on vascular function.

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The Effect of Salsalate Therapy on Endothelial Function in a Broad Range of Subjects

Cited by 33 publications

References 59 publications

Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk

Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk

Endothelial dysfunction and vascular disease - a 30th anniversary update

Endothelial Dysfunction in Type 2 Diabetes: Targeting Inflammation

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