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991.
Cathepsin K Knockout Mitigates High-Fat Diet–Induced Cardiac Hypertrophy and Contractile Dysfunction
Yinan Hua Yingmei Zhang Julia Dolence Guo-Ping Shi Jun Ren Sreejayan Nair 《Diabetes》2013,62(2):498-509
The cysteine protease cathepsin K has been implicated in pathogenesis of cardiovascular disease. We hypothesized that ablation of cathepsin K protects against obesity-associated cardiac dysfunction. Wild-type mice fed a high-fat diet exhibited elevated heart weight, enlarged cardiomyocytes, increased left ventricular wall thickness, and decreased fractional shortening. All these changes were reconciled in cathepsin K knockout mice. Cathepsin K knockout partly reversed the impaired cardiomyocyte contractility and dysregulated calcium handling associated with high-fat diet. Additionally, cathepsin K knockout alleviated whole-body glucose intolerance and improved insulin-stimulated Akt phosphorylation in high-fat diet–fed mice. High-fat feeding increased the expression of cardiac hypertrophic proteins and apoptotic markers, which were inhibited by cathepsin K knockout. Furthermore, high-fat feeding resulted in cathepsin K release from lysosomes into the cytoplasm. In H9c2 myoblasts, silencing of cathepsin K inhibited palmitic acid–induced release of cytochrome c from mitochondria and expression of proapoptotic signaling molecules. Collectively, our data indicate that cathepsin K contributes to the development of obesity-associated cardiac hypertrophy and may represent a potential target for the treatment to obesity-associated cardiac anomalies.Obesity is an emerging health problem worldwide and is an independent risk factor for the pathogenesis of cardiovascular disease (1–3). Uncorrected obesity predisposes individuals to myocardial damage characterized as cardiac hypertrophy and contractile dysfunction (4–6). Although several theories have been postulated to explain obesity-associated cardiac anomalies, including alterations in myocardial substrate utilization, neurohumoral activation, mitochondrial dysfunction, oxidative stress, impaired insulin signaling, and lipotoxicity, the underlying pathological mechanisms remain elusive (7). Obesity is known to trigger a number of adverse cellular signaling processes in the heart, such as re-expression of fetal genes, intracellular Ca2+ mishandling, derangement in proteins responsible for excitation-contraction coupling, and cardiac fatty acid oxidation (8,9). Obesity also triggers changes in extracellular matrix (10) and apoptosis of cardiomyocytes (11), which also can contribute to heart failure.Cathepsins are cysteine proteases that are ubiquitously expressed in various tissues and are implicated in the pathogenesis of cardiovascular diseases (12–14). Primarily located in lysosomes, cathepsins are transported between different cellular organelles and are released into the circulation under pathological conditions such as diabetes and atherosclerosis (15,16) or after lysosomal leakage caused by reactive oxygen species. Once released from lysosomes, cathepsins trigger apoptotic cell death by activating caspases and releasing proapoptotic factors from the mitochondria (17). Elevated levels of cathepsins S and K have been reported in atherosclerotic plaques, neointimal lesions, and in the failing heart in both humans and animals (18–21). Elevated levels of myocardial cathepsin B has been reported in individuals with dilated cardiomyopathy (22). However, deficiency of cathepsin L has been associated with cardiomyopathy whereas overexpression of this protease was shown to retard cardiac hypertrophy (23), suggesting distinct regulation of cardiac tissue by various cathepsins. Recent studies have shown that cathepsin K is elevated in adipose tissues of obese humans and mice and inhibition of cathepsin K attenuated body weight gain and serum glucose and insulin levels in obese mice (24). Given that cardiac dysfunction is a major complication of obesity, this study was designed to test the hypothesis that ablation of cathepsin K protects against high-fat diet–induced cardiac dysfunction. Our studies reveal that deletion of cathepsin K attenuates obesity-associated cardiac hypertrophy and contractile dysfunctions. 相似文献
992.
Xiaoling Lin Lianxi Qu Zhuo Chen Chuanliang Xu Dingwei Ye Qiang Shao Xiang Wang Jun Qi Zhiwen Chen Fangjian Zhou Meilin Wang Zhong Wang Dalin He Denglong Wu Xin Gao Jianlin Yuan Gongxian Wang Yong Xu Guozeng Wang Pei Dong Yang Jiao Jin Yang Jun Ou‐Yang Haowen Jiang Yao Zhu Shancheng Ren Zhengdong Zhang Changjun Yin Qijun Wu Ying Zheng Aubrey R. Turner Sha Tao Rong Na Qiang Ding Daru Lu Rong Shi Jielin Sun Fang Liu S. Lilly Zheng Zengnan Mo Yinghao Sun Jianfeng Xu 《The Prostate》2013,73(2):169-175
993.
994.
Li Zhuo Wenwen Ren Wenge Li Guming Zou Jianhua Lu 《International urology and nephrology》2013,45(1):173-179
Objectives
The outcome and the therapy of patients with diabetes mellitus (DM), diabetic nephropathy (DN), and non-diabetic renal disease (NDRD) are quite different, so the differential diagnosis is of considerable importance. To evaluate the usefulness of renal biopsy in type 2 diabetic patients, we examined the relationship between the clinical parameters and the histopathological findings in different age groups.Methods
Renal biopsy specimens and clinical and laboratory data from 216 patients with type 2 DM were evaluated. According to their age, three groups were defined: 17–35 years (group I), 36–59 years (group II), and more than 60 years (group III).Results
The study showed that, beside the duration of diabetes, other clinical parameters were not significantly different between the three groups. Chronic nephritic syndrome was the most common clinical manifestation in group I (44.1 %) and in group II (34.0 %). Among patients in group III, we found a high prevalence of chronic renal failure (34.3 %) and nephrotic syndrome (28.6 %). Consistent with the clinical manifestations, IgA nephropathy was the most common pathologic finding in group I (29.4 %) and in group II (34.7 %), whereas the most frequent abnormalities in group III were membranous nephropathy (25.7 %) and tubulointerstitial lesions (14.3 %). Overall, among these patients, 14 cases were diagnosed with DN (6.5 %), 179 with NDRD (82.9 %), while 23 had concurrent DN and NDRD (10.7 %).Conclusions
Our results indicated that the clinical manifestations and pathologic findings in type 2 diabetic patients in different age groups have different features. This study emphasized the usefulness of renal biopsy for determining the pattern of renal damage and thus for the overall management of type 2 diabetic patients. 相似文献995.
996.
Ren X Akiyoshi K Grafe MR Vandenbark AA Hurn PD Herson PS Offner H 《Metabolic brain disease》2012,27(1):7-15
Although inflammatory responses increase stroke severity, the role of immune cells specific for central nervous system (CNS)
antigens remains controversial. Disruption of the blood–brain barrier (BBB) during stroke allows CNS antigens to leak into
the peripheral circulation and enhances access of circulating leukocytes to the brain, including those specific for CNS antigens
such as myelin oligodendrocyte glycoprotein (MOG) that can induce experimental autoimmune encephalomyelitis (EAE). We here
demonstrate for the first time that myelin reactive splenocytes specific for MOG transferred into severe combined immunodeficient
(SCID) mice can migrate into the infarct hemisphere of recipients subjected to 60 min middle cerebral artery occlusion (MCAO)
and 96 h reperfusion; moreover these cells exacerbate infarct volume and worsen neurological deficits compared to animals
transferred with na?ve splenocytes. These findings indicate that autoimmunity in the CNS can exert detrimental injury on brain
cells and worsen the damage from ischemic stroke. 相似文献
997.
The aim of the prospective study was to explore the safety and effectiveness of external beam radiation therapy (EBRT) in three patients with biopsy proven primary pulmonary amyloidosis, including two tracheobronchial amyloidosis patients and one primary parenchymal amyloidosis patient. All three patients were treated to 24 Gy in 12 fractions utilizing CT simulation and 3-D planning. All three patients had significant improvement in clinical symptoms, radiological imaging as well as pulmonary function tests. The improvement in the clinical symptoms was evident in 2 days. Toxicities related to EBRT were not observed during the follow-up range from 42 to 54 months. EBRT to 24 Gy was safe and effective in the three patients with primary pulmonary amyloidosis, and resulted in rapid relief of pulmonary symptoms. 相似文献
998.
Lambert R Saito H Lucas E Sankaranarayanan R 《European journal of gastroenterology & hepatology》2012,24(6):605-612
The incidence of digestive cancer, including cancer of the esophagus, stomach, colon, and liver, is analyzed in developing and less developed countries in Africa, Asia, the Caribbean, and Latin America. The analysis is based on cancer registries for observed values, on a recent monograph published at International Agency for Research on Cancer and on the GLOBOCAN 2008 database for estimations. For all tumor sites analyzed, the incidence is lower in these countries than in developed countries of Europe, North America, and Japan. The 5-year relative survival from digestive cancer is also lower. In developing countries, there is room for prevention of cancer burden through lifestyle interventions and through improved early detection of cancer. 相似文献
999.
1000.