Perivascular Adipose Tissue and Atherosclerosis

Traditionally, it is believed that white adipose tissues serve as energy storage, heat insulation, and mechanical cushion, whereas non-shivering thermogenesis occurs in brown adipose tissue. Recent evidence revealed that adipose tissue secretes many types of cytokines, called as adipocytokines, which modulate glucose metabolism, lipid profile, appetite, fibrinolysis, blood pressure, and inflammation. Most of the arteries are surrounded by perivascular adipose tissue (PVAT). PVAT has been thought to be simply a structurally supportive tissue for vasculature. However, recent studies showed that PVAT influences vasodilation and vasocontraction, suggesting that PVAT regulates vascular tone and diameter. Adipocytokines secreted from PVAT appear to have direct access to the adjacent arterial wall by diffusion or via vasa vasorum. In fact, PVAT around atherosclerotic lesions and mechanically-injured arteries displayed inflammatory cytokine profiles, suggesting that PVAT functions to promote vascular lesion formation. Many clinical studies revealed that increased accumulation of epicardial adipose tissue (EAT), which surrounds coronary arteries, is associated with coronary artery disease. In this review article, we will summarize recent findings about potential roles of PVAT in the pathogenesis of atherosclerosis, particularly focusing on a series of basic and clinical studies from our laboratory

Rupture of pes anserine bursa

Pes anserinus pain syndrome is a common, clinically defined condition that is characterized by pain around the medial knee and tenderness over the upper medial tibia. The anserine bursa could be the site of proliferative and inflammatory conditions due to knee osteoarthritis, leading to pain and fluid retention. However, rupture of the pes anserinus is rare. Herein, we present a case of rupture of the pes anserine bursa in a patient with pes anserine pain syndrome and osteoarthritis. Physicians should consider rupture of the pes anserine bursa as a differential diagnosis of acute unilateral lower leg swelling

Functional analysis of the mutations in the human cardiac beta-myosin that are responsible for familial hypertrophic cardiomyopathy. Implication for the clinical outcome

More than 30 missense mutations in the beta-cardiac myosin heavy chain gene have been shown to be responsible for familial hypertrophic cardiomyopathy. To clarify the effects of these point mutations on myosin motor function, we expressed wild-type and mutant human beta-cardiac myosin heavy chains in insect cells with human cardiac light chains. The wild-type myosin was well purified with similar enzymatic and motor activities to those of the naturally isolated V3 cardiac myosin. Arg249--\u3eGln and Arg453--\u3eCys mutations resulted in decreased actin translocating activity (61 and 23% of the wild-type, respectively) with decreased intrinsic ATPase activity. Arg403--\u3eGln mutation greatly decreased actin translocating activity (27% of wild type) with a 3.3-fold increased dissociation constant for actin, while intrinsic ATPase activity was unchanged. Val606--\u3eMet mutation only mildly affected the actin translocating activity as well as ATPase activity of myosin. The degree of deterioration by each mutation was closely correlated with the prognosis of the affected kindreds, indicating that myosin dysfunction caused by the point mutations is responsible for the pathogenesis of the disease. Structure/function relationship of myosin is discussed

Adipose Tissue and Atherosclerosis

Accumulating evidence revealed that adipose tissues secrete pro-inflammatory and anti-inflammatory humoral factors, called as adipocytokines. Most of the arteries are surrounded by perivascular adipose tissue (PVAT), which influences adjacent artery by secreting adipocytokines. PVATs are supposed to be athero-protective under healthy conditions, whereas PVATs are athero-promoting in obesity. Recent clinical studies suggested that coronary atherosclerosis is associated with increased volume of epicardial adipose tissue (EAT), PVAT of coronary artery. It was suggested that enhanced inflammation in EAT is also associated with vasospastic angina. In this review article, we will summarize recent findings about potential roles of EAT in the pathogenesis of coronary atherosclerosis

キュウセイ シンキン コウソク ノ ショキ チリョウ : キュウメイ ノ レンサ

The chain of survival refers to a series of actions that, when put into motion, reduce the mortality associated with cardiac arrest. Someone must witness the cardiac arrest and immediately call to the emergency services（early access）. Bystander CPR should be provided immediately after collapse of the patient（early CPR）. Public access defibrillation may be the key to improving survival rates in out-of-hospital cardiac arrest（early defibrillation）. Patients should be transferred to specialized hospitals, which provide advanced cardiac life support（early advanced care）. In most of the cases, minimization of myocardial damage by early re-canalization is associated with better prognosis. The four interdependent links in the chain of survival is essential to reduce mortality rate in patients with acute myocardial infarction

Tokushima Plan for Promotion of Measures Against Cerebrovascular and Cardiovascular Diseases

Cerebrovascular diseases including stroke and cardiovascular diseases are the leading causes of death in Japan, which together account for 23.2% of the total number of deaths in 2018. The major causes of the need for long-term care in Japan are also cerebrovascular disease（16.1%）and cardiovascular disease（4.5%）, which together account for more than one-fifth of the total. Medical expenses for both cerebrovascular and cardiovascular disease account for ≈20% of the total, which is the highest by injury/illness classification. The Cerebrovascular and Cardiovascular Disease Control Act, of Japanese national law, was promulgated by a legislative act on December 14, 2018, and enacted on December 1, 2019. On the basis of the Cerebrovascular and Cardiovascular Disease Control Act, the Ministry of Health, Labour and Welfare, Japan, published the Japanese National Plan for Promotion of Measures Against Cerebrovascular and Cardiovascular Disease on October 27, 2020. It has indicated both problems in the current situation and individual measures to address the problems. The Japanese National Plan includes 3 major measures : spreading awareness of prevention measures and accurate information on cerebrovascular and cardiovascular disease ; enhancing service provision systems related to health, medical care, and welfare services ; and promoting research on cerebrovascular and cardiovascular disease. The 2 main goals of the Japanese National Plan are to extend healthy life expectancy by 3 years by 2040 compared with 2016 and to decrease age-adjusted mortality of cerebrovascular and cardiovascular disease. The average life expectancy and healthy life expectancy for both men and women increased by 0.67 to 1.72 years from 2010 to 2016 in Japan. In 2016, the unhealthy period which is defined as differences between healthy life expectancy（men, 72.14 years ; women, 74.49 years）and average life expectancy（men, 80.98 years ; women, 87.14 years）was large : ≈8.8 years for men and ≈12.4 years for women. Therefore, extending healthy life expectancy is a primary goal of the Japanese National Plan. Based on this national plan, the Tokushima Plan for Promotion of Measures Against Cerebrovascular and Cardiovascular Diseases is developed through the meetings of the Tokushima Council for Promotion of Measures Against Cerebrovascular and Cardiovascular Diseases, parliamentary associated meetings, and public comments. The council is composed of patients with cerebrovascular or cardiovascular disease ; those engaged in emergency services and health, medical, or welfare services ; and those with academic experience. Here, we describe outline of the Tokushima Plan for Promotion of Measures Against Cerebrovascular and Cardiovascular Disease

カンドウミャク シッカン ノ ビョウタイ カイメイ ト アタラシイ シンダン チリョウ ギジュツ ノ カイハツ

Recent evidence suggests that acute coronary syndrome（ACS）results from plaque rupture in most of the cases. Vulnerable plaques are characterized by thinning of fibrous cap, increased lipid content, decreased smooth muscle cell content, and enhanced infiltration of inflammatory cells. However, the molecular mechanism of plaque destabilization is not fully understood. Thus, there is no established method to predict and prevent ACS. We have been studying the pathogenesis of plaque progression and destabilization, using animal models and clinical specimen. ApoE-deficient mice showed exaggerated atherosclerotic lesions with aging. Accumulation of macrophages in adventitia was first detected prior to plaque formation. Proliferation of vasa vasorum was observed only after atherosclerotic lesion formation. Local delivery of an angiogenic growth factor promoted lesion formation with enhanced neovascularization in the adventitia. Periadventitial fat is distributed ubiquitously around arteries. By using fat transplantation method, we found that periadventitial fat may protect against neointimal formation after angioplasty under physiological conditions and that inflammatory changes in the periadventitial fat may play a crucial role in the pathogenesis of vascular disease accelerated by obesity. Elucidation of the pathogenesis of coronary artery diseases leads to development of new strategies to diagnose and treat acute coronary syndrome

ジュンカンキ シッカン ノ ヨボウ ト セイカツ シュウカン

Recent evidence suggests that acute coronary syndrome（ACS）results from plaque rupture in most of the cases. Vulnerable plaques are characterized by thinning of fibrous cap, increased lipid content, decreased smooth muscle cell content, and enhanced infiltration of inflammatory cells.Coronary risk factors such as hypertension, dyslipidemia, diabetes, and smoking, promote these processes, which result in cardiovascular complications. Rigorous control of lifestyle-related diseases is important for the prevention of cardiovascular diseases.However, the molecular mechanism of plaque destabilization is not fully understood. Thus,there is no established method to predict and prevent ACS. We have been studying the pathogenesis of plaque progression and destabilization using animal models and clinical specimen.In this symposium, I will present our recent findings on the molecular mechanism of plaque rupture and discuss effective strategies to diagnose and prevent ACS

Expanding role of deoxyribonucleic acid-sensing mechanism in the development of lifestyle-related diseases

In lifestyle-related diseases, such as cardiovascular, metabolic, respiratory, and kidney diseases, chronic inflammation plays a causal role in their pathogenesis; however, underlying mechanisms of sterile chronic inflammation are not well-understood. Previous studies have confirmed the damage of cells in these organs in the presence of various risk factors such as diabetes, dyslipidemia, and cigarette smoking, releasing various endogenous ligands for pattern recognition receptors. These studies suggested that nucleic acids released from damaged tissues accumulate in these tissues, acting as an endogenous ligand. Undamaged DNA is an integral factor for the sustenance of life, whereas, DNA fragments, especially those from pathogens, are potent activators of the inflammatory response. Recent studies have indicated that inflammatory responses such as the production of type I interferon (IFN) induced by DNA-sensing mechanisms which contributes to self-defense system in innate immunity participates in the progression of inflammatory diseases by the recognition of nucleic acids derived from the host, including mitochondrial DNA (mtDNA). The body possesses several types of DNA sensors. Toll-like receptor 9 (TLR9) recognizes DNA fragments in the endosomes. In addition, the binding of DNA fragments in the cytosol activates cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS), resulting in the synthesis of the second messenger cyclic GMP-AMP (cGAMP). The binding of cGAMP to stimulator of interferon genes (STING) activates NF-κB and TBK-1 signaling and consequently the production of many inflammatory cytokines including IFNs. Numerous previous studies have demonstrated the role of DNA sensors in self-defense through the recognition of DNA fragments derived from pathogens. Beyond the canonical role of TLR9 and cGAS-STING, this review describes the role of these DNA-sensing mechanism in the inflammatory responses caused by endogenous DNA fragments, and in the pathogenesis of lifestyle-related diseases