Sumiharu Sakamoto

Inhibition of Development of Abdominal Aortic Aneurysm by Glycolysis Restriction

Objective—The mechanisms underlying abdominal aortic aneurysm development remain unknown. We hypothesized that acceleration of glucose metabolism with the upregulation of glucose transporters is associated with abdominal aortic aneurysm development. Methods and Results—Enhanced accumulation of the modified glucose analogue 18 fluoro-deoxyglucose by positron emission tomography imaging in the human abdominal aortic aneurysm was associated with protein expressions of glucose transporters-1 and -3, assessed by Western blot. The magnitude of glucose transporter-3 expression was correlated with zymographic matrix metalloproteinase-9 activity. Intraperitoneal administration of glycolysis inhibitor with 2-deoxyglucose significantly attenuated the dilatation of abdominal aorta induced by periaortic application of CaCl2 in C57BL/6J male mice or reduced the aneurysmal formation in angiotensin II-infused apolipoprotein E knockout male mice. In monocytic cell line induced by phorbol 12-myristate 13-acetate or ex vivo culture obtained from human aneurysmal tissues, 2-deoxyglucose abrogated the matrix metalloproteinase-9 activity and interleukin-6 expression in these cells/tissues. Moreover, 2-deoxyglucose attenuated the survival/proliferation of monocytes and the adherence of them to vascular endothelial cells. Conclusion—This study suggests that the enhanced glycolytic activity in aortic wall contributes to the pathogenesis of aneurysm development. In addition, pharmacological intervention in glycolytic activity might be a potential therapeutic target for the disorder.

Cardiac hypertrophy is exacerbated in aged mice lacking the osteoprotegerin gene

AIMS Osteoprotegerin (OPG) may play a role in the progression of cardiac hypertrophy and heart failure. However, its pathophysiological role in changes in cardiac structure and function with ageing remains to be elucidated. METHODS AND RESULTS We conducted experiments using 2.5- and 12-month-old OPG(-/-) mice and age-matched wild-type (WT) mice and compared the morphology and function of the left ventricle (LV). Both 2.5- and 12-month-old OPG(-/-) mice showed a higher systolic blood pressure and a greater heart weight/body weight ratio than age-matched WT mice. Twelve-month-old OPG(-/-) mice had a significantly larger LV chamber and reduced wall thickness compared with age-matched WT mice, and contractile function was decreased. The morphological differences were accompanied by an increase in the number of apoptotic cells and activation of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in the LV of 12-month-old OPG(-/-) mice. Correspondingly, OPG small interfering RNA induced the expressions of TRAIL and cleaved caspase-3 in cultured cardiac myocytes. In addition, these mice revealed a decrease in interstitial fibrosis, activation of matrix metalloproteinase (MMP)-2 and tissue inhibitors of MMP-1 and -2, and inactivation of procollagen α1 synthesis. Moreover, intraperitoneal administration of recombinant OPG to either 2.5- or 12-month-old OPG(-/-) mice for 28 days led to partial improvement of LV structure and function without affecting systolic blood pressure. CONCLUSION These results suggest that OPG plays a role in preserving myocardial structure and function with ageing through a reduction in apoptosis and preservation of the matrix structure. In addition, this appears to be independent of effects on the vasculature.

Angiotensin II Stimulation of Cardiac Hypertrophy and Functional Decompensation in Osteoprotegerin-Deficient Mice.

Circulating and myocardial expressions of receptor activator of nuclear factor-&kgr;b ligand and osteoprotegerin are activated in heart failure; however, it remains to be determined their pathophysiological roles on left ventricular structure and function in interaction with renin–angiotensin system. We conducted experiments using 8-week-old osteoprotegerin−/− mice and receptor activator of nuclear factor-&kgr;b ligand-transgenic mice to assess whether they affect the angiotensin II–induced left ventricular remodeling. Subcutaneous infusion of angiotensin II to osteoprotegerin−/− mice progressed the eccentric hypertrophy, resulting in left ventricular systolic dysfunction for 28 days, and this was comparable with wild-type mice, showing concentric hypertrophy, irrespective of equivalent elevation of systolic blood pressure. The structural alteration was associated with reduced interstitial fibrosis, decreased procollagen &agr;1 and syndecan-1 expressions, and the increased number of apoptotic cells in the left ventricle, compared with wild-type mice. In contrast, angiotensin II infusion to the receptor activator of nuclear factor-&kgr;b ligand-transgenic mice revealed the concentric hypertrophy with preserved systolic contractile function. Intraperitoneal administration of human recombinant osteoprotegerin, but not subcutaneous injection of anti-receptor activator of nuclear factor-&kgr;b ligand antibody, to the angiotensin II–infused osteoprotegerin−/− mice for 28 days ameliorated the progression of heart failure without affecting systolic blood pressure. These results underscore the biological activity of osteoprotegerin in preserving myocardial structure and function during the angiotensin II–induced cardiac hypertrophy, independent of receptor activator of nuclear factor-&kgr;b ligand activity. In addition, the antiapoptotic and profibrotic actions of osteoprotegerin that emerged from our data might be involved in the mechanisms.

Impact of Age-Dependent Adventitia Inflammation on Structural Alteration of Abdominal Aorta in Hyperlipidemic Mice

Background The adventitia is suggested to contribute to vascular remodeling; however, the site-selective inflammatory responses in association with the development of atherosclerosis remain to be elucidated. Methods and Results Wild-type or apolipoprotein E knockout male C57BL/6J background mice were fed standard chow for 16, 32, and 52 weeks, and the morphology of the aortic arch, descending aorta, and abdominal aorta was compared. Atheromatous plaque formation progressed with age, particularly in the aortic arch and abdominal aorta but not in the descending aorta. In addition, we found that the numbers of macrophages, T-lymphocytes, and microvessels, assessed by anti-F4/80, CD3, and CD31 antibodies, were higher in the adventitia of the abdominal aorta at 52 weeks. These numbers were positively correlated with plaque formation, but negatively correlated with elastin content, resulting in the enlargement of the total vessel area. In aortic tissues, interleukin-6 levels increased in the atheromatous plaque with age, whereas the level of regulated on activation, normal T cell expressed and secreted (RANTES) increased with age, and compared with other sites, it was particularly distributed in inflammatory cells in the adventitia of the abdominal aorta. Conclusion This study suggests that adventitial inflammation contributes to the age-dependent structural alterations, and that the activation/inactivation of cytokines/chemokines is involved in the process.

Mast cell density and distribution in human abdominal aortic aneurysm

Atherosclerosis exhibits many inflammatory characteristics, in which macrophages and T-lymphocytes are found at the shoulder region of atherosclerotic plaque, and are associated with its rupture and thrombosis (Libby et al. 2010). On the other hand, abdominal aortic aneurysm (AAA) shows distinct histological features; inflammatory cell infiltration was observed predominantly at the outer media and adventitia (Michel et al. 2010). Several experimental studies have suggested important roles of inflammatory cells (macrophages, T-lymphocytes and neutrophils) in AAA development (Longo et al. 2002; Xiong et al. 2004; Eliason et al. 2005). Mast cell, unique effector components of the immune system, play a critical role in defending hosts against pathogens by releasing a number of immunoregulatory mediators (Marshall & Jawdat 2004). Mast cells synthesize a number of substances, which include histamine, heparin, tryptase, chymase, carboxypeptidase, cathepsin G, leukotriene C4, prostaglandin D2, tumor necrosis factor-α and interleukin (IL)4,-5,-6,-13, some of which are stored in secretory vesicles (Krishnaswamy et al. 2006). Recently, mast cells have been recognized not only to be involved in host defense but also to initiate the inflammatory response by recruiting macrophages and T-lymphocytes (von Stebut et al. 2003; Henz et al. 2001) and by releasing pro-inflammatory cytokines, growth factors, angiogenic mediators and proteases (Krishnaswamy et al. 2006). Specifically, tryptase and chymase have been examined for their unique biological actions to modulate extracellular matrix formation and induce apoptosis of vascular smooth muscle cells (Cairns & Walls 1997; Leskinen et al. 2001; Tchougounova et al. 2005). In this chapter, we characterize mast cell density and distribution in the human aneurysmal abdominal aorta, compared with atherosclerotic abdominal aorta, and discuss the potential role of this type of cell to understand the pathophysiology of AAA.

A high-fat diet is deleterious to mice under glycolysis restriction

It is debated whether carbohydrate restriction has metabolic advantage for its variable weight loss. Five-week-old male mice fed a high-fat diet and receiving a glycolytic inhibitor, 2-deoxyglucose, died within 9 days. They exhibited greater decreases in rectal temperature, appetite, and decline in body weight accompanied by increasing total cholesterol level than the other groups. This study suggests that carbohydrate is necessary for adequate physical and metabolic performance when lipid-rich diet is loaded.

18F-Fluorodeoxyglucose Positron Emission Tomography 10 Days Before Onset of Aortic Dissection

Received June 6, 2017; revised manuscript received June 30, 2017; accepted July 13, 2017; released online August 22, 2017 Time for primary review: 7 days Department of Internal Medicine, Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, Miyazaki (T.T., M.Y., S.S., T.I., K.K.); Department of Radiology, Faculty of Medicine, Fukuoka University, Fukuoka (S.N.), Japan Mailing address: Toshihiro Tsuruda, MD, PhD, Department of Internal Medicine, Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki 889-1692, Japan. E-mail: ttsuruda@med.miyazakiu.ac.jp ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp 18F-Fluorodeoxyglucose Positron Emission Tomography 10 Days Before Onset of Aortic Dissection

SIGNIFICANCE OF CARDIAC TROPONIN T LEVELS IN SUPRAVENTRICULAR TACHYCARDIA

Background: Cardiac troponin T is sensitive and specific markers of myocardial injury and is used routinely for the diagnosis of acute coronary syndrome. Recently, the magunitude of troponin T levels in heart failure patients has been reported to correlate with severity of the disease and with adverse outcomes. They may suggest ongoing myocardial damage. In supraventricular tachycardia, common atrial flutter (AFL) and atrial tachycardia (AT) often produce changes in cardiac function and structure, but atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT) do not. To our knowledge, there are no reports about the relationship between the levels of troponin T and the types of supraventricular tachycardia. We examined the clinical usefulness of previously unmeasurable levels of troponin T (hs-TnT) by using highly sensitive assay for the differential diagnosis of supraventricular tachycardia.