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

Jaetaek Kim(김재택) 한국실험동물학회 2012 한국실험동물학회 학술발표대회 논문집 Vol.2012 No.8

Therapeutic strategy for atherosclerosis based on bone-vascular axis hypothesis

Kim, Jeong-Min,Lee, Wang-Soo,Kim, Jaetaek Elsevier 2020 Pharmacology & therapeutics Vol.206 No.-

<P><B>Abstract</B></P> <P>As the world's older population grows, the disease burden of atherosclerosis is rapidly increasing, causing significant morbidity and mortality worldwide. Despite recent improvements in the control of vascular risk factors, a significant number of patients still suffer from vascular events and the progression of atherosclerosis. Aging also results in decreased bone mineral density. Since bones are a home for hematopoietic stem cells as well as reservoirs of the minerals required for vascular integrity, it is conceivable that a novel therapeutic strategy for atherosclerosis treatment can be developed by focusing on the complex interplay between bones and blood vessels. The correction of mineral dyshomeostasis, disrupted bone marrow microenvironments, and triggered inflammatory cell production provide potential therapeutic options against the atherosclerotic process. This review highlights recent advances in our understanding of the bone-vascular link and discusses new insights into treatment targets for atherosclerosis.</P>

Connexin43 and zonula occludens-1 are targets of Akt in cardiomyocytes that correlate with cardiac contractile dysfunction in Akt deficient hearts

Ock, Sangmi,Lee, Wang Soo,Kim, Hyun Min,Park, Kyu-Sang,Kim, Young-Kook,Kook, Hyun,Park, Woo Jin,Lee, Tae Jin,Abel, E.D.,Kim, Jaetaek Elsevier 2018 Biochimica et biophysica acta Vol.1864 No.4

<P><B>Abstract</B></P> <P>While deletion of <I>Akt1</I> results in a smaller heart size and <I>Akt2</I> <SUP>−/−</SUP> mice are mildly insulin resistant, <I>Akt1</I> <SUP>−/−</SUP>/<I>Akt2</I> <SUP>−/−</SUP> mice exhibit perinatal lethality, indicating a large degree of functional overlap between the isoforms of the serine/threonine kinase Akt. The present study aimed to determine the cooperative contribution of Akt1 and Akt2 on the structure and contractile function of adult hearts. To generate an inducible, cardiomyocyte-restricted Akt2 knockout (KO) model, <I>Akt2</I> <SUP>flox/flox</SUP> mice were crossed with tamoxifen-inducible MerCreMer transgenic (MCM) mice and germline <I>Akt1</I> <SUP>−/−</SUP> mice to generate the following genotypes:<I>Akt1</I> <SUP>+/+</SUP>; <I>Akt2</I> <SUP>flox/flox</SUP> (WT), <I>Akt2</I> <SUP>flox/flox</SUP>; α-MHC-MCM (<I>iAkt2</I> KO), <I>Akt1</I> <SUP>−/−</SUP>, and <I>Akt1</I> <SUP>−/−</SUP>; <I>Akt2</I> <SUP>flox/flox</SUP>; α-MHC-MCM mice (<I>Akt1</I> <SUP>−/−</SUP>/<I>iAkt2</I> KO). At 28 days after the first tamoxifen injection, <I>Akt1</I> <SUP>−/−</SUP>/<I>iAkt2</I> KO mice developed contractile dysfunction paralleling increased atrial and brain natriuretic peptide (ANP and BNP) levels, and repressed mitochondrial gene expression. Neither cardiac fibrosis nor apoptosis were detected in <I>Akt1</I> <SUP>−/−</SUP>/<I>iAkt2</I> KO hearts. To explore potential molecular mechanisms for contractile dysfunction, we investigated myocardial microstructure before the onset of heart failure. At 3 days after the first tamoxifen injection, <I>Akt1</I> <SUP>−/−</SUP>/<I>iAkt2</I> KO hearts showed decreased expression of connexin43 (Cx43) and connexin-interacting protein zonula occludens-1 (ZO-1). Furthermore, Akt1/2 silencing significantly decreased both Cx43 and ZO-1 expression in cultured neonatal rat cardiomyocytes in concert with reduced beating frequency. Akt1 and Akt2 are required to maintain cardiac contraction. Loss of Akt signaling disrupts gap junction protein, which might precipitate early contractile dysfunction prior to heart failure in the absence of myocardial remodeling, such as hypertrophy, fibrosis, or cell death.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Cardiac <I>Akt1</I> <SUP>-/-</SUP>/<I>iAkt2</I> KO in mice reduces cardiac size and induces contractile dysfunction without myocardial remodeling. </LI> <LI> <I>Akt1</I> <SUP>-/-</SUP>/<I>iAkt2</I> KO hearts revealed decreased expression of Cx43 and connexin-interacting protein ZO-1. </LI> <LI> Akt isoforms may play important roles to maintain cardiac contractile function through gap junction protein stability. </LI> </UL> </P>

Prostaglandin A₂-induced Apoptosis is Not Inhibited by Heme Oygenase-1 in U2OS Cells

Kyoung-Won Ko(고경원),Sun-Young Lee(이선영),Ji-Hyun Ahn(안지현),Jaetaek Kim(김재택),In-Kyung Kim(김인경),Ho-Shik Kim(김호식) 한국생명과학회 2008 생명과학회지 Vol.18 No.11

Prostaglandin A₂ (PGA₂)는 사람 골육종 세포인 U2OS 세포주에서 apoptosis와 heme oxygenase (HO)-1의 발현을 함께 유도하였다. PGA₂에 의한 apoptosis는 HO-1의 과도한 발현이나 HO-1에 대한 small interfering RNA에 의한 발현저하에 의하여 변동되지 않았으나 H₂O₂에 의한 세포사망은 HO-1의 발현 수준에 반비례하여 변동되었다. 또한 thiol antioxidant인 N-acetyl-L-cysteine (NAC)은 PGA₂에 의한 세포사망과 HO-1의 발현 증가를 모두 차단하였지만, non-thiol antioxidant인 butylated hydroxyanisole (BHA)과 ascorbic acid는 세포사망과 HO-1의 발현 유도를 차단하지 않았다. 이와 같은 결과들은 PGA₂는 산화성 손상에 의해서가 아니라 PGA₂의 thiol-reactivity에 의하여 apoptosis와 HO-1의 발현을 유도하며, HO-1의 발현은 PGA₂에 의한 apoptosis와는 독립적인 현상이거나 기능적으로 apoptosis 유도의 하부에 위치하고 apoptosis의 진행에는 기여하지 않을 것이라는 것을 시사해 준다. Prostaglandin A₂ (PGA₂), one of cyclopentenone PGs, induced both apoptosis and heme oxygenase (HO)-1 expression in U2OS cells. PGA₂-induced apoptosis was not perturbed by either over-expression or knock-down of HO-1, whereas H₂O₂-induced cell death was inversely modulated by the expression level of HO-1. In addition, N-acetyl-L-cysteine (NAC), a thiol antioxidant, blocked both apoptosis and HO-1 expression induced by PGA₂. But, non-thiol antioxidants like butylated hydorxyanisole (BHA) and ascorbic acid did not block either apoptosis or HO-1-induction. Taken together, these results suggest that PGA₂ induces both apoptosis and HO-1 expression, which are critically related to the thiol-reactivity of PGA₂, but not oxidative stress, and HO-1 expression may be independent or functionally located downstream of apoptosis by PGA₂ without contribution to apoptosis progression.

제2형 당뇨병 및 비만증 환자에서 Interleukin-6 유전자 다형성

김재택,최승진,이미경,박애자,오연상,신순현 대한당뇨병학회 2002 Diabetes and Metabolism Journal Vol.25 No.5

연구배경:Interleukin(IL)­6는 지방세포를 포함한 여러 종류의 세포에서 분비되는 사이토카인이며, 비만 환자에서 분비량이 증가된다고 알려져 있다. 최근 IL­6의 5' flanking 위치의 유전자 다형성이 보고되었으며, 이는 인슐린저항성과 지질대사 이상과 관련이 있다고 한다. 본 연구는 한국인 제2형 당뇨병 환자와 비만증 환자에서 IL­6 유전자 다형성의 빈도와 이들 질환의 발병과의 관련성을 알아보고자 하였다. 방법:과체중이거나 비만한 성인 64명, 비비만형 제2형 당뇨병 환자 63명 및 비만형 제2형 당뇨병 환자 50명의 임상양상을 조사하고, PCR­RFLP법으로 IL­6유전자 다형성을 분석하였다. 결과:1)총 177명의 대상자 중 176명의 GG(99.4%)형, 1명의 GC(0.57%)형이 발견되었으나, CC형은 없었다. 2)유전자형 빈도는 G형이 99.7%, C형이 0.28%이었다. 3)비만한 제2형 당뇨병 환자에서 C형의 유전자형 빈도는 1.02%이었다. 4)C형의 유전자형 빈도는 코카시안에 비해 매우 낮았다. 결론:한국인에서 IL­6 유전자 다형성은 비만이나 제2형 당뇨병과의 관련을 찾을 수 없었다. Background: Interleukin (IL)-6 is produced by many different cell types, including adipose tissue, and the release is greater in obese subjects. Recently, it has been reported that polymorphism in the 5’ flanking region of the IL-6 gene may contribute to the insulin resistance and lipid abnormality. However, there are limited number of studies reported on the relationship between IL-6 polymorphism and insulin resistance syndrome. Therefore, the aim of this study was to examine the relationships among this polymorphism, obesity and diabetes in Korean subjects. Methods: We examined a total of 177 Korean individuals, including 113 type 2 diabetic subjects. Sixty-three subjects were non-obese diabetics(age; 56.4± 9.8 yr, body mass index(BMI); 22.5± 1.7 kg/㎡), 50 of them were obese diabetic subjects(age: 54.8± 10.7 yr, BMI; 27.6±2.2 kg/㎡), and 64 were overweight or obese subjects (age; 49.1± 11.4 yr, BMI; 25.4±1.5 kg/㎡). We evaluated IL-6 gene polymorphism using PCR-restriction fragment length polymorphism. Results: There were 176 G G (99.4%), 1 G C (0.56%) and 0 CC(0%) individuals, and the allele frequencies were 99.7% for G and 0.28% for C. Allele frequencies of C in obese diabetic subjects were 1.02%. The frequency of C allele was substantially lower than that reported in Caucasian. Conclusion: This results suggest that the IL-6 polymorphism is not associated with obesity nor diabetes in Korean subjects(J Kor Diabetes Asso 25;337~342, 2001).

Statin-induced liver and muscle toxicities

이왕수,Jaetaek Kim 대한독성 유전단백체 학회 2019 Molecular & cellular toxicology Vol.15 No.1

Purpose of review: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are a class of lipid-lowering medications by inhibiting the enzyme HMG-CoA reductase. Statins are important drugs for the prevention of cardiovascular disease. The prominent value of statins is well established during the past three decades. The efficacy and safety of statins have been evaluated in many large randomized controlled trials. Recent findings: Currently, emerging concerns with statin-induced liver toxicity (SILT) and muscle toxicity (SIMT) have been introduced. However, exact mechanisms of SILT and SIMT have not been well understood. Moreover, there is an increasing concern currently about their safety associated with genetic polymorphisms. Thus, this article reviews the mechanisms of statin-drug interactions and their adverse effects with a particular focus on SILT and SIMT. It is recommended that the specific pharmacology for the different statins should be understood to maximize their benefit and minimize statin-induced toxicity. Significant toxicity may be induced by statin-drug interactions, and understanding how certain drugs interact with statins will help physicians in safely prescribing these agents.

Cardiotoxicity associated with tyrosine kinase-targeted anticancer therapy

Wang-Soo Lee,Jaetaek Kim 대한독성 유전단백체 학회 2018 Molecular & cellular toxicology Vol.14 No.3

Purpose of review: Tyrosine kinase inhibitors (TKIs) have shown clear survival benefits as effective targeted therapies in various hematological and solid malignancies. Important evidence, however, has shown that TKIs may lead to adverse effects such as cardiovascular toxicities, via off-target as well as on-target mechanisms. This review presents an overview of TKI-induced cardiotoxicity mechanisms, clinical manifestations, diagnosis, monitoring, and management options. Furthermore, we discuss current preclinical efforts and future investigations into alternative therapeutics for minimizing the cardiotoxicities associated with tyrosine kinase-targeted therapies. Recent findings: Accompanying with the significant improvements toward targeted anticancer treatment, cardiotoxicity-related adverse effects are increasingly reported and have become an important public health issue. The TKI-induced cardiovascular toxicities include myocardial ischemia, heart failure, QT prolongation, and hypertension. Thus, the early awareness of cardiotoxicities, initiation of appropriate management, and close follow-up, may enhance the benefits of TKI therapy.

Effect of sodium salicylate on COX-2 expression in neonatal rat cardiomyocytes

Sangmi Ock,Hyun Min Kim,이왕수,Jihyun Ahn,Jaetaek Kim 대한독성 유전단백체 학회 2018 Molecular & cellular toxicology Vol.14 No.1

Salicylates, one of the oldest medicinal compounds known to humans, have been reported to show anti-inflammatory effects via cyclooxygenase (COX) inhibition. However, the pathophysiological role of COX-2 in the heart is conflicting, and the role of sodium salicylate in the regulation of cardiac inflammation has not yet been elucidated. We aimed to investigate the effect of salicylate on COX-2 expression and its associated prostaglandin production using cultured neonatal rat cardiomyocytes. The cells were incubated in the presence or absence of sodium salicylate (8 mM). Treatment with sodium salicylate significantly increased COX-2 expression at both mRNA and protein levels, induced prostaglandin D2 release, and increased TNF-α mRNA expression in cardiomyocytes. In addition, salicylate treatment induced cardiomyocyte hypertrophy. Taken together, we demonstrated that salicylate induced COX-2 expression, which in turn resulted in the regulation of expression of several inflammatory mediators in cardiomyocytes.

Health-related quality of life in elderly population with diabetes mellitus.

( Hongyeul Lee ),( Hyun Min Kim ),( Jaetaek Kim ) 대한내과학회 2015 대한내과학회 추계학술대회 Vol.2015 No.1

Objective: This study aimed to investigate the relationship between diabetes mellitus and health-related quality of life (HRQoL) in elderly population, furthermore, the impact of comorbidities and glycemic control level on HRQoL in elderly patients with diabetes. Methods: Data from the 5th Korean National Health and Nutrition Examination Survey (KNHANES) of 2010-2012 were used in this study. Presence of comorbidities including hypertension, dyslipidemia, cardiovascular diseases, chronic kidney disease, chronic liver disease, chronic lung disease, and various types of cancer were analyzed. EuroQol 5D index score (EQ-5D) was used for assessment of health-related quality of life. Logistic regressions were used to explore determinants for the lowest quintile HRQoL scales in the diabetes group. Results: A total of 4742 subjects over 65 years of age (2031 men and 2711 women; mean age 72.9 ± 5.7 years) were included. Prevalence of diabetes mellitus was 22.7%, and prediabetes was 34.3% in this population. The mean EQ-5D score was lower in the diabetes group (0.84 ± 0.19) than the others (0.86 ± 0.18, p=0.001). The patients with diabetes had more comorbidities (1.73 ± 1.23) compared to those with normal glucose or prediabetes (1.09 ± 1.16, 1.42 ± 1.20, respectively). Among the 1076 patients with diabetes, EQ-5D score was associated with the numbers of comorbidities, however, there was no relationship with HbA1c level and EQ-5D score. In logistic analysis, age(OR 1.1, 95% CI, 1.1 to 1.2), male gender(OR 1.9, 95% CI, 1.3 to 2.8), and number of comorbidities(OR 1.4, 95% CI, 1.2 to 1.7) were associated with poor HRQoL, in contrast, HbA1c level, duration of diabetes, BMI, and treatment modality did not affect the HRQoL. Conclusions: Diabetes was associated with impaired HRQoL and multiple comorbidities in elderly population. Furthermore, in the elderly diabetic patients, glycemic control status was not associated with HRQoL, the degree of comorbid conditions was an important factor for defining HRQoL.

Diabetic cardiomyopathy: where we are and where we are going

( Wang-soo Lee ),( Jaetaek Kim ) 대한내과학회 2017 The Korean Journal of Internal Medicine Vol.32 No.3

The global burden of diabetes mellitus and its related complications are currently increasing. Diabetes mellitus affects the heart through various mechanisms including microvascular impairment, metabolic disturbance, subcellular component abnormalities, cardiac autonomic dysfunction, and a maladaptive immune response. Eventually, diabetes mellitus can cause functional and structural changes in the myocardium without coronary artery disease, a disorder known as diabetic cardiomyopathy (DCM). There are many diagnostic tools and management options for DCM, although it is difficult to detect its development and effectively prevent its progression. In this review, we summarize the current research regarding the pathophysiology and pathogenesis of DCM. Moreover, we discuss emerging diagnostic evaluation methods and treatment strategies for DCM, which may help our understanding of its underlying mechanisms and facilitate the identification of possible new therapeutic targets.