Jihyun Ahn

Receptor activator of nuclear factor-κB ligand is a novel inducer of myocardial inflammation

AIMS Although increased levels of myocardial receptor activator of nuclear factor (NF)-κB ligand (RANKL) have been reported in heart failure, the role of this pathway in mediating activation of inflammatory pathways during myocardial remodelling is less well understood. This study sought to determine the role of myocardial RANKL in regulating cytokine expression. METHODS AND RESULTS A marked increase in RANKL expression occurred as early as 6h following transverse aortic constriction (TAC) in mouse hearts and persisted at 3 and 17 days. An increase in tumour necrosis factor-α (TNF-α), interleukin (IL)-1α, and IL-1β was observed in the hypertrophied hearts only at 3 or 17 days after TAC. Treatment with losartan significantly attenuated TAC-induced cardiac hypertrophy, in parallel with decreased expression of RANKL, TNF-α, IL-1α, and IL-1β. Furthermore, injection of a RANKL-neutralizing monoclonal antibody attenuated RANKL-induced cytokine expression. RANKL stimulated expression of TNF-α, IL-1α, and IL-1β in neonatal rat cardiomyocytes via activation of NF-κB. RANKL-induced NF-κB activation and expression of these cytokines were both attenuated when RANK, receptor for RANKL, or TRAF2 or TRAF6, adaptors for RANK, was silenced by siRNA. Furthermore, inhibitors of phospholipase C (PLC), protein kinase C (PKC), and inhibitor of κB kinase also significantly inhibited RANKL-induced cellular activities, but inhibitors of phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, or p38 mitogen-activated protein kinase were without effect. CONCLUSION Our data demonstrate for the first time that the pressure-overloaded myocardium generates RANKL, which induces TNF-α, IL-1α, and IL-1β production via a RANK-TRAF2/TRAF6-PLC-PKC-NF-κB-mediated autocrine mechanism.

Mechanisms and Consequences of Inflammatory Signaling in the Myocardium

To further understand chronic heart disease, such as heart failure and cardiomyopathy, we must fully define signaling pathways within the myocardium. Recent studies suggest that some forms of heart disease are associated with a chronic low-grade inflammation that promotes adverse ventricular remodeling and correlates with disease progression. Several inflammatory mediators, including TNF-α, IL-1β, and IL-6, are involved in cardiac injury subsequent to myocardial ischemia and reperfusion, sepsis, viral myocarditis, and transplant rejection. Once activated, components of the inflammatory response can have both beneficial and deleterious effects on the heart. In this review, we discuss the complex inflammatory signaling pathways in the myocardium and potential therapeutic implications.

Reliability and validity of a self-reported measure of medication adherence in patients with type 2 diabetes mellitus in Korea

Objective This study examined the psychometric properties of the Korean version of the eight-item Morisky Medication Adherence Scale (MMAS-8) to measure adherence to diabetes medication in patients with type 2 diabetes mellitus. Methods The English version of the MMAS-8 was translated into Korean and administered to patient with type 2 diabetes mellitus via face-to-face interviews, conducted by an independent interviewer. Patient characteristics and glycosylated haemoglobin (HbA1c) levels were assessed at the same clinic visit. A proportion of patients was randomly selected for 2-week test-retest reliability via telephone interviews. Convergent validity of the MMAS-8 against a four-item MMAS, correlations with HbA1c levels and construct validity of the MMAS-8 were evaluated. Results In total, 317 patients were included; 70 completed the 2-week test–retest interview. Internal consistency reliability was moderate and test–retest reliability of the MMAS-8 was excellent, although a ceiling effect was detected. Good convergent validity was shown by the high correlation of the new scale scores with the original MMAS-4. A significant association was found between MMAS-8 scores and HbA1c levels. Using glycaemic control as a gold standard, sensitivity was 74.1% and specificity was 38.3%. Explanatory factor analysis identified three dimensions of the scale. Conclusions In light of acceptable reliability and validity, the MMAS-8 is a simple and quick method for the assessment of medication adherence among patient with type 2 diabetes mellitus, in a busy clinic setting.

IGF-1 receptor deficiency in thyrocytes impairs thyroid hormone secretion and completely inhibits TSH-stimulated goiter

Although thyroid‐stimulating hormone (TSH) is known to be a major regulator of thyroid hormone biosynthesis and thyroid growth, insulin‐like growth factor 1 (IGF‐1) is required for mediating thyrocyte growth in concert with TSH in vitro. We generated mice with thyrocyte‐selective ablation of IGF‐1 receptor (TIGF1RKO) to explore the role of IGF‐1 receptor signaling on thyroid function and growth. In 5‐wk‐old TIGF1RKO mice, serum thyroxine (T4) concentrations were decreased by 30% in concert with a 43% down‐regulation of the monocarboxylate transporter 8 (MCT8), which is involved in T4 secretion. Despite a 3.5‐fold increase in circulating concentrations of TSH, thyroid architecture and size were normal. Furthermore, thyrocyte area was increased by 40% in WT thyroids after 10 d TSH injection, but this effect was absent in TSH‐injected TIGF1RKO mice. WT mice treated with methimazole and sodium perchlorate for 2 or 6 wk exhibited pronounced goiter development (2.0 and 5.4‐fold, respectively), but in TIGF1RKO mice, goiter development was completely abrogated. These data reveal an essential role for IGF‐1 receptor signaling in the regulation of thyroid function and TSH‐stimulated goitrogenesis.—Ock, S., Ahn, J., Lee, S. H., Kang, H., Offermanns, S., Ahn, H. Y., Jo, Y.S., Shong, M., Cho, B. Y., Jo, D., Abel, E. D., Lee, T. J., Park, W. J., Lee, I.‐K., Kim, J. IGF‐1 receptor deficiency in thyrocytes impairs thyroid hormone secretion and completely inhibits TSH‐stimulated goiter. FASEB J. 27, 4899–4908 (2013). www.fasebj.org

Deletion of IGF-1 Receptors in Cardiomyocytes Attenuates Cardiac Aging in Male Mice

IGF-1 receptor (IGF-1R) signaling is implicated in cardiac hypertrophy and longevity. However, the role of IGF-1R in age-related cardiac remodeling is only partially understood. We therefore sought to determine whether the deletion of the IGF-1R in cardiomyocytes might delay the development of aging-associated myocardial pathologies by examining 2-year-old male cardiomyocyte-specific IGF-1R knockout (CIGF1RKO) mice. Aging was associated with the induction of IGF-1R expression in hearts. Cardiomyocytes hypertrophied with age in wild-type (WT) mice. In contrast, the cardiac hypertrophic response associated with aging was blunted in CIGF1RKO mice. Concomitantly, fibrosis was reduced in aged CIGF1RKO compared with aged WT hearts. Expression of proinflammatory cytokines such as IL-1α, IL-1β, IL-6, and receptor activator of nuclear factor-κB ligand was increased in aged WT hearts, but this increase was attenuated in aged CIGF1RKO hearts. Phosphorylation of Akt was increased in aged WT, but not in aged CIGF1RKO, hearts. In cultured cardiomyocytes, IGF-1 induced senescence as demonstrated by increased senescence-associated β-galactosidase staining, and a phosphoinositide 3-kinase inhibitor inhibited this effect. Furthermore, inhibition of phosphoinositide 3-kinase significantly prevented the increase in IL-1α, IL-1β, receptor activator of nuclear factor-κB ligand, and p21 protein expression by IGF-1. These data reveal an essential role for the IGF-1-IGF-1R-Akt pathway in mediating cardiomyocyte senescence.

Surface Drainage Simulation Model for Irrigation Districts Composed of Paddy and Protected Cultivation

The objectives of this study were to develop a hydrologic simulation model to estimate surface drainage for irrigation districts consisting of paddy and protected cultivation, and to evaluate the applicability of the developed model. The model consists of three sub-models; agricultural supply, paddy block drainage, and protected cultivation runoff. The model simulates daily total drainage as the sum of paddy field drainage, irrigation canal drainage, and protected cultivation runoff at the outlets of the irrigation districts. The agricultural supply sub-model was formulated considering crop water requirement for growing seasons and agricultural water management loss. Agricultural supply was calculated for use as input data for the paddy block sub-model. The paddy block drainage sub-model simulates paddy field drainage based on water balance, and irrigation canal drainage as a fraction of agricultural supply. Protected cultivation runoff is calculated based on NRCS (Natural Resources Conservation Service) curve number method. The Idong reservoir irrigation district was selected for surface drainage monitoring and model verification. The parameters of model were calibrated using a trial and error technique, and validated with the measured data from the study site. The model can be a useful tool to estimate surface drainage for irrigated districts consisting of paddy and protected cultivation.

Prostaglandin A2 activates intrinsic apoptotic pathway by direct interaction with mitochondria in HL-60 cells

HL-60 cells treated by prostaglandin (PG) A(2) showed characteristics of apoptosis such as accumulation of hypodiploid and annexin V positive cells, condensed and fragmented nuclei, cytochrome c (Cyt C) release from mitochondria and activation of caspase-1, -2, -3, -7 and -9. PGA(2)-induced cell death was rescued by inhibitors of caspase-9 and -3, but PGA(2)-induced Cyt C release was not prevented by caspase inhibitors. During Cyt C release by PGA(2), mitochondrial transmembrane potential was maintained and mitochondrial permeability transition pore was not formed. In addition, anti-apoptotic BCL-2 family proteins like BCL-2 and BCL-XL, and ROS scavengers including ascorbic acid and 2,2,6,6-tetramethyl-1-piperidinyloxy were not able to inhibit Cyt C release as well as apoptosis by PGA(2). Finally, it was shown that PGA(2)-induced Cyt C release in vitro from purified mitochondria in the absence of cytosolic components. Furthermore, thiol-containing compounds such as N-acetylcysteine, l-cysteine and monothioglycerol prevented Cyt C release, and hence induction of apoptosis. Taken together, these results suggest that PGA(2) activates intrinsic apoptotic pathway by directly stimulating mitochondrial outer membrane permeabilization to release Cyt C, in which thiol-reactivity of PGA(2) plays a pivotal role.

Nutritional Status and Cardiac Autophagy

Autophagy is necessary for the degradation of long-lasting proteins and nonfunctional organelles, and is activated to promote cellular survival. However, overactivation of autophagy may deplete essential molecules and organelles responsible for cellular survival. Lifelong calorie restriction by 40% has been shown to increase the cardiac expression of autophagic markers, which suggests that it may have a cardioprotective effect by decreasing oxidative damage brought on by aging and cardiovascular diseases. Although cardiac autophagy is critical to regulating protein quality and maintaining cellular function and survival, increased or excessive autophagy may have deleterious effects on the heart under some circumstances, including pressure overload-induced heart failure. The importance of autophagy has been shown in nutrient supply and preservation of energy in times of limitation, such as ischemia. Some studies have suggested that a transition from obesity to metabolic syndrome may involve progressive changes in myocardial inflammation, mitochondrial dysfunction, fibrosis, apoptosis, and myocardial autophagy.

Prevalence of the Metabolic Syndrome in Type 2 Diabetic Patients

연구배경: 국내 제2형 당뇨병환자에서의 대사증후군 유병률에 대한 보고가 많지 않았다. 본 연구는 최근 대학병원에서 진료중인 제2형 당뇨병환자를 대상으로 대사증후군의 유병률과 관련된 인자를 알아보고자 하였다. 방법: 2006년 국내 대학병원 13개 기관의 내분비내과를 방문한 제2형 당뇨병환자 4,240명(남성 2,033명, 여성 2,207명, 평균연령 58.7±11.3세, 당뇨병의 이환기간 8.9±7.6년)을 대상으로 2005년 발표된 AHA/NHLBI의 대사증후군 진단기준과 대한비만학회에서 제시한 복부비만(허리둘레) 기준을 적용하여 대사증후군으로 정의하였다. 결과: 대상 환자의 77.9%가 대사증후군을 동반하였고, 남성(76.7%)에 비해 여성(78.9%)에서 대사증후군의 유병률이 약간 높았으나 연령을 보정한 후 차이는 없었다. 대사증후군의 구성요소 개수의 평균은 2.4 (±1.1)개 이었다. 대사증후군의 구성요소 각각의 유병률은 복부비만 56.8%, 고중성지방혈증 42.0%, 저고밀도지단백 콜레스테롤혈증 65.1%, 고혈압 74.9%로 나타나 고혈압이 가장 흔하였다. 복부비만과 고혈압은 여성에서 남성보다 높은 빈도를 보였고, 저고밀도지단백 콜레스테롤혈증은 남성에서 더 높게 나타났다. 대사증후군은 나이가 증가함에 따라 증가하며, 특히 여자에서 뚜렷한 증가를 보였다. 한편 당뇨병 이환기간에 따른 대사증후군 유병률은 차이가 없었다. 대사증후군의 동반을 결정하는 인자를 알기 위해 다중로지스틱회귀분석을 시행한 결과 전신비만이 동반된 경우 6.3배, 나이가 증가할수록, 구체적으로 40대 1.5배, 50대 1.5배, 60대 2.2배, 70대 이상 3.4배 높은 것으로 나타났다. 결론: 한국인 제2형 당뇨병환자에서 대사증후군은 77.9%이었고, 대사증후군은 비만이 있고, 나이가 40대 이상일수록 높은 것으로 나타났다.

A Case of Teriparatide on Pregnancy-Induced Osteoporosis

Pregnancy-induced osteoporosis is a rare disorder characterized by fragility fracture and low bone mineral density (BMD) during or shortly after pregnancy, and its etiology is still unclear. We experienced a case of a 39-year-old woman who suffered from lumbago 3 months after delivery. Biochemical evidence of increased bone resorption is observed without secondary causes of osteoporosis. Radiologic examination showed multiple compression fractures on her lumbar vertebrae. We report a case of patient with pregnancy-induced osteoporosis improved her clinical symptom, BMD and bone turnover marker after teriparatide therapy.