Abstract
Stroke is a major cause of mortality and disability worldwide. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Therefore, antihypertensive treatments are recommended for the prevention of stroke. Three angiotensin receptor blockers (ARBs), telmisartan, irbesartan and candesartan, inhibit the expression of the receptor for advanced glycation end-products (RAGE), which is one of the pleiotropic effects of these drugs. High mobility group box 1 (HMGB1) is the ligand of RAGE, and has been recently identified as a lethal mediator of severe sepsis. HMGB1 is an intracellular protein, which acts as an inflammatory cytokine when released into the extracellular milieu. Extracellular HMGB1 causes multiple organ failure and contributes to the pathogenesis of hypertension, hyperlipidemia, diabetes mellitus, atherosclerosis, thrombosis, and stroke. This is the first review of the literature evaluating the potential of three ARBs for the HMGB1-RAGE axis on stroke therapy, including prevention and acute treatment. This review covers clinical and experimental studies conducted between 1976 and 2013. We propose that ARBs, which inhibit the HMGB1/RAGE axis, may offer a novel option for prevention and acute treatment of stroke. However, additional clinical studies are necessary to verify the efficacy of ARBs.
Highlights
Stroke was the second most common cause of death worldwide in 2011, resulting in 6.2 million deaths (11.4% of the total) in statistics of the World Health Organization
Telmisartan, irbesartan, and candesartan are angiotensin receptor blockers (ARBs), which are widely used to treat patients with HT. These ARBs inhibit the expression of the receptor for advanced glycation end-products (RAGE), which is induced by an inflammatory factor, tumor necrosis factor-α (TNF-α), in human endothelial cells [5]
The study results suggested that telmisartan and valsartan are associated with a lower risk of admission to hospital for stroke, heart failure, or acute myocardial infarction in older patients with diabetes mellitus (DM) [71]
Summary
Stroke was the second most common cause of death worldwide in 2011, resulting in 6.2 million deaths (11.4% of the total) in statistics of the World Health Organization. Telmisartan, irbesartan, and candesartan are angiotensin receptor blockers (ARBs), which are widely used to treat patients with HT These ARBs inhibit the expression of the receptor for advanced glycation end-products (RAGE), which is induced by an inflammatory factor, tumor necrosis factor-α (TNF-α), in human endothelial cells [5]. Grossin et al reported that modulating RAGE expression by correcting endothelial dysfunction is achievable by drugs already used for HT or DM treatment, such as ARBs [5] These ARBs may be useful in the prevention of stroke. HMGB1 is a member of the “alarmin” family, a group of endogenous factors that act from the extracellular space after release, and activate the inflammatory response through the binding of membrane receptors [25,26]. Clinically approved drugs, such as telmisartan, irbesartan, and candesartan, which inhibit the HMGB1/RAGE axis, may be useful in the prevention and treatment of various diseases
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