p38 MAP Kinase Inhibition in Cardiovascular Disease
p38 MAP Kinase Inhibition in Cardiovascular Disease
p38 mitogen-activated protein kinases (p38 MAPKs) are key signalling molecules that regulate cellular behavior in response to environmental stresses. They regulate pro-inflammatory cytokines and therefore p38 MAPKs are implicated in the pathogenesis of many inflammatory-driven conditions, including atherosclerosis. Therapeutic inhibition of p38 MAPKs to attenuate inflammation has been the focus of comprehensive research in the last 2 decades, following the discovery of p38α as the molecular target of pyrindinyl imidazole compounds, which suppress the cytokines tumor necrosis factor-α and interleukin-1. The potential of p38 MAPK inhibitors was initially explored within archetypal inflammatory conditions such as rheumatoid arthritis and Crohn's disease, but early studies demonstrated poor clinical efficacy and unacceptable side effects. Subsequent clinical trials evaluating different p38 MAPK inhibitor compounds in disease models such as chronic obstructive pulmonary disease (COPD) and atherosclerosis have shown potential clinical efficacy. This review aims to provide succinct background information regarding the p38 MAPK signaling pathway, a focus of p38 MAPKs in disease, and a brief summary of relevant preclinical studies. An update of human clinical trial experience encompassing a clinically orientated approach, dedicated to cardiovascular disease follows. It provides a current perspective of the therapeutic potential of p38 MAPK inhibitors in the cardiovascular domain, including safety, tolerability, and pharmacokinetics.
Inflammation and Cardiovascular Disease
Cardiovascular disease is the leading cause of death globally, and is associated with significant healthcare utilization and economic costs. Atherosclerosis is a key element contributing to this burden, and inflammation is viewed as a pivotal component of the initiation and progression of atheroma. This may explain why inflammatory conditions, which are accompanied by elevated levels of circulating biomarkers and pro-inflammatory cytokines, have been associated with increased cardiovascular risk. However, inflammation is also thought to have other nonatherosclerotic detrimental effects on the cardiovascular system, including aortic stiffening and endothelial dysfunction.
Inflammation is therefore considered an important component in the progression of cardiovascular disease and has emerged as a focus for novel therapeutic agents. There is a substantial body of work from preclinical models establishing this rationale and this has recently translated to clinical trials investigating 'anti-inflammatory' drugs in cardiovascular disease. The SATURN (Study of Coronary Atheroma By Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin) and JUPITER (Justification for the Use of statin in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) trials, for example, suggest biomarkers of inflammation are associated with adverse cardiovascular prognosis, and statin therapy (as an 'antiinflammatory' agent) can reduce cardiovascular risk by attenuating inflammation. The 'anti-inflammatory' effects of statins are thought to account for reduced C-reactive protein (CRP) levels observed with therapy, and this is considered to be independent of the statins' therapeutic effect of lowering serum low-density lipoprotein (LDL) cholesterol, and commonly referred to as a 'pleiotropic effect'. The CANTOS (Canakinumab Anti-Thrombosis Outcome Study) trial, which is currently recruiting participants, aims to determine whether pharmacological inhibition of inflammation alone (without any effect on lipid pathways) can truly impact clinical outcomes. It is designed to evaluate the effect of canakinumab (a human monoclonal antibody designed to neutralize the bioactivity of human interleukin [IL]-1β) on rates of recurrent cardiovascular events in stable coronary artery disease subjects with persistent inflammation quantified by elevated CRP levels (>2 mg/L).
Within this context, inhibition of p38 mitogen-activated protein kinases (MAPKs) to attenuate inflammation is a prospective therapeutic target worthy of further consideration. p38 MAPKs are key signaling molecules in cellular responses to external stresses and regulation of proinflammatory cytokines, and are thus implicated in inflammatory mechanisms of disease, including those affecting the heart and vasculature. p38 MAPK inhibitors as a prospective therapeutic class have been examined in pre-clinical models and, more recently, in clinical studies of cardiovascular disease.
This review provides background information on the p38 MAPK family, discusses the isoforms of p38 and subsequently focuses on the relevance of p38 in disease, in particular the cardiovascular system. Evaluation of strategies for the pharmacological inhibition of p38 and an in-depth review of human clinical trial experience to date within the cardiovascular domain is also explored.
Abstract and Introduction
Abstract
p38 mitogen-activated protein kinases (p38 MAPKs) are key signalling molecules that regulate cellular behavior in response to environmental stresses. They regulate pro-inflammatory cytokines and therefore p38 MAPKs are implicated in the pathogenesis of many inflammatory-driven conditions, including atherosclerosis. Therapeutic inhibition of p38 MAPKs to attenuate inflammation has been the focus of comprehensive research in the last 2 decades, following the discovery of p38α as the molecular target of pyrindinyl imidazole compounds, which suppress the cytokines tumor necrosis factor-α and interleukin-1. The potential of p38 MAPK inhibitors was initially explored within archetypal inflammatory conditions such as rheumatoid arthritis and Crohn's disease, but early studies demonstrated poor clinical efficacy and unacceptable side effects. Subsequent clinical trials evaluating different p38 MAPK inhibitor compounds in disease models such as chronic obstructive pulmonary disease (COPD) and atherosclerosis have shown potential clinical efficacy. This review aims to provide succinct background information regarding the p38 MAPK signaling pathway, a focus of p38 MAPKs in disease, and a brief summary of relevant preclinical studies. An update of human clinical trial experience encompassing a clinically orientated approach, dedicated to cardiovascular disease follows. It provides a current perspective of the therapeutic potential of p38 MAPK inhibitors in the cardiovascular domain, including safety, tolerability, and pharmacokinetics.
Introduction
Inflammation and Cardiovascular Disease
Cardiovascular disease is the leading cause of death globally, and is associated with significant healthcare utilization and economic costs. Atherosclerosis is a key element contributing to this burden, and inflammation is viewed as a pivotal component of the initiation and progression of atheroma. This may explain why inflammatory conditions, which are accompanied by elevated levels of circulating biomarkers and pro-inflammatory cytokines, have been associated with increased cardiovascular risk. However, inflammation is also thought to have other nonatherosclerotic detrimental effects on the cardiovascular system, including aortic stiffening and endothelial dysfunction.
Inflammation is therefore considered an important component in the progression of cardiovascular disease and has emerged as a focus for novel therapeutic agents. There is a substantial body of work from preclinical models establishing this rationale and this has recently translated to clinical trials investigating 'anti-inflammatory' drugs in cardiovascular disease. The SATURN (Study of Coronary Atheroma By Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin) and JUPITER (Justification for the Use of statin in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) trials, for example, suggest biomarkers of inflammation are associated with adverse cardiovascular prognosis, and statin therapy (as an 'antiinflammatory' agent) can reduce cardiovascular risk by attenuating inflammation. The 'anti-inflammatory' effects of statins are thought to account for reduced C-reactive protein (CRP) levels observed with therapy, and this is considered to be independent of the statins' therapeutic effect of lowering serum low-density lipoprotein (LDL) cholesterol, and commonly referred to as a 'pleiotropic effect'. The CANTOS (Canakinumab Anti-Thrombosis Outcome Study) trial, which is currently recruiting participants, aims to determine whether pharmacological inhibition of inflammation alone (without any effect on lipid pathways) can truly impact clinical outcomes. It is designed to evaluate the effect of canakinumab (a human monoclonal antibody designed to neutralize the bioactivity of human interleukin [IL]-1β) on rates of recurrent cardiovascular events in stable coronary artery disease subjects with persistent inflammation quantified by elevated CRP levels (>2 mg/L).
Within this context, inhibition of p38 mitogen-activated protein kinases (MAPKs) to attenuate inflammation is a prospective therapeutic target worthy of further consideration. p38 MAPKs are key signaling molecules in cellular responses to external stresses and regulation of proinflammatory cytokines, and are thus implicated in inflammatory mechanisms of disease, including those affecting the heart and vasculature. p38 MAPK inhibitors as a prospective therapeutic class have been examined in pre-clinical models and, more recently, in clinical studies of cardiovascular disease.
This review provides background information on the p38 MAPK family, discusses the isoforms of p38 and subsequently focuses on the relevance of p38 in disease, in particular the cardiovascular system. Evaluation of strategies for the pharmacological inhibition of p38 and an in-depth review of human clinical trial experience to date within the cardiovascular domain is also explored.
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