Role of p38 MAPK in Atherosclerosis and Aortic Valve Sclerosis

Abstract

Atherosclerosis and aortic valve sclerosis are cardiovascular diseases with an increasing prevalence in western societies. Statins are widely applied in atherosclerosis therapy, whereas no pharmacological interventions are available for the treatment of aortic valve sclerosis. Therefore, valve replacement surgery to prevent acute heart failure is the only option for patients with severe aortic stenosis. Both atherosclerosis and aortic valve sclerosis are not simply the consequence of degenerative processes, but rather diseases driven by inflammatory processes in response to lipid-deposition in the blood vessel wall and the aortic valve, respectively. The p38 mitogen-activated protein kinase (MAPK) is involved in inflammatory signaling and activated in response to various intracellular and extracellular stimuli, including oxidative stress, cytokines, and growth factors, all of which are abundantly present in atherosclerotic and aortic valve sclerotic lesions. The responses generated by p38 MAPK signaling in different cell types present in the lesions are diverse and might support the progression of the diseases. This review summarizes experimental findings relating to p38 MAPK in atherosclerosis and aortic valve sclerosis and discusses potential functions of p38 MAPK in the diseases with the aim of clarifying its eligibility as a pharmacological target.

Keywords: MAPK; aortic valve sclerosis; aortic valve stenosis; atherosclerosis; p38.

Figure 1

Functional involvement of p38 mitogen-activated protein kinase (MAPK) signaling in calcific aortic valve disease (CAVD) and atherosclerosis. Upper left: CAVD lesion. Schematic cross-section of an aortic valve leaflet composed of the fibrosa, spongiosa, and ventricularis tissue layers. The layers are dispersed by matrix producing valve interstitial cells (VICs) and lined by endothelial cells on both sides which face the aorta or the left ventricle. Lipids accumulate mainly in the collagen-rich fibrosa layer, which is also where the calcification develops. Upper right: atherosclerotic lesion. Schematic cross-section of the vessel wall containing an atherosclerotic plaque. The vessel wall consists of a collagen-rich intima layer lined by endothelial cells that are in direct contact with the blood flow. The underlying media layer contains vascular smooth muscle cells (VSMCs) that contract and dilate in response to nerve signals from the adventitia layer, thereby regulating local blood pressure. The adventitia contains nerves and blood vessels that supply the VSMCs. Atherosclerotic plaques develop in the intima layer and are stabilized by VSMCs from the media. Lower panel: functions attributed to p38 MAPK activity in different immune cells present in CAVD and atherosclerotic lesions. TGFβ: transforming growth factor β; BMP: bone morphogenic protein; EnMT: endothelial to mesenchymal transition; NKT: natural killer T cells; TLR4: toll-like receptor 4; TCR: T cell receptor; IFNγ: interferon γ; BCR: B cell receptor; mLDL: modified LDL.