Hiroto Miura, M.D.

Associate Professor

Contact Information

Research Interests

KCa3.1 channels mediate the development of atherosclerosis
Atherosclerosis is the ultimate pathological consequence of vascular remodeling and is associated with the activation of vascular smooth muscle cells (VSMCs) and inflammatory cells. In atherosclerosis, VSMCs switch from a contractile state into cells that proliferate and migrate from the medial layer to form the fibrous cap overlying the atheromatous core of lipid in atherosclerotic plaques. Monocytes infiltrate the plaques, differentiate into macrophages, and contribute to atherogenesis by producing reactive oxygen species (ROS), proteases, cytokines, and complement. Plasmacytoid dendritic cells in plaques activate infiltrating T lymphocytes, which in turn activate macrophages and kill ECs. The development of new anti-atherosclerotic therapies that modulate a target common to these pathophysiologically activated cells in atherogenesis - VSMCs, monocytes/macrophages, and T lymphocytes - would have substantial medical value.
The intermediate-conductance calcium-activated potassium channel composed of 4 KCa3.1 subunits and 4 calmodulin molecules is expressed in VSMCs, T lymphocytes, macrophages, and ECs, where it regulates membrane potential and calcium signaling. We and others have reported that KCa3.1 mRNA expression is significantly increased in coronary arteries of rats with myocardial infarction or hypertension and of swine with early atherosclerosis. KCa3.1 blockers inhibit VSMC proliferation and migration, macrophage function, T cell activation, and EC proliferation. In vivo blockade of KCa3.1 prevents vascular restenosis following angioplasty by suppressing VSMC proliferation in rats, alleviates the symptoms of experimental autoimmune encephalomyelitis by reducing T cell-mediated immune responses in mice, and inhibits angiogenesis by suppressing EC proliferation that contributes to the progression of advanced atherosclerotic plaques. We examine that KCa3.1 might serve as a novel therapeutic target shared by these cell types implicated in atherogenesis. The link between KCa3.1 and atherosclerosis represents a new investigative direction that has the potential to shed new light on our understanding of the fundamental abnormalities underlying this disease, and highlights a promising new therapeutic approach for atherosclerosis.

Shear-stress regulation of endothelial CD73
Atherosclerosis, a chronic inflammatory disease involving endothelial expression of adhesion molecules and pro-atherosclerotic cytokines and the recruitment of leukocytes, preferentially occurs in areas of oscillatory shear stress (OSS), whereas high laminar shear stress (LSS) is atheroprotective. Adenosine, a metabolite of adenine nucleotides (ATP, ADP and AMP), is another anti-atherosclerotic molecule, since it shares many properties with nitric oxide (NO) to prevent the development of atherosclerosis. In the circulation, adenine nucleotides are extracellularly released from a variety of cell types such as ECs, platelets and leukocytes in response to physiological stimuli including shear stress. Extracellular adenine nucleotides (pro-inflammatory mediators) are rapidly dephosphorylated to adenosine by ectonucleotidases anchored to EC surface. CD73 (ecto-5' nucleotidase) is a key enzyme for extracellular production of adenosine (AMP ® adenosine). CD73 is a cell surface protein anchored to the membrane via glycosyl phosphatidyl inositol (GPI), that is released as the soluble form or microparticle (MP) to the circulation. The biological function of CD73 on EC protection is not fully understood. This project defines the hypothesis that shear stress regulates cell surface CD73 expression in ECs. Investigations on the differential regulatory mechanisms by LSS and OSS may lead to our understanding of the fundamental abnormalities underlying atherosclerosis, and highlights a new therapeutic approach for this disease.