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Atherosclerosis MMPs

Dmitrii V Kalinin, Stefan Wagner, Burkhard Riemann, Sven Hermann, Frederike Schmidt, Christoph Becker-Pauly, Stefan Rose-John, Michael Schäfers, Ralph Holl
As dysregulation of matrix metalloproteinase (MMP) activity is associated with a wide range of pathophysiological processes like cancer, atherosclerosis, and arthritis, MMPs represent a valuable target for the development of new therapeutics and diagnostic tools. We herein present the chiral pool syntheses, in vitro evaluation and SAR studies of a series of D- and L-proline- as well as of (4<i>R</i>)-4-hydroxy-L-proline-derived MMP inhibitors possessing general formula <b>1</b>. Some of the synthesized hydroxamic acids were found to be potent MMP inhibitors with IC<sub>50</sub>-values in the nanomolar range, also demonstrating no off-target effects towards the other tested Zn<sup>2+</sup>-dependent metalloproteases (ADAMs and meprins)...
October 3, 2016: Journal of Medicinal Chemistry
Samuel Hernandez-Anzaldo, Vesna Brglez, Bianca Hemmeryckx, Dickson Leung, Janos G Filep, Jean E Vance, Dennis E Vance, Zamaneh Kassiri, Roger H Lijnen, Gérard Lambeau, Carlos Fernandez-Patron
BACKGROUND: The development of atherosclerosis is strongly linked to disorders of cholesterol metabolism. Matrix metalloproteinases (MMPs) are dysregulated in patients and animal models with atherosclerosis. Whether systemic MMP activity influences cholesterol metabolism is unknown. METHODS AND RESULTS: We examined MMP-9-deficient (Mmp9(-/-)) mice and found them to have abnormal lipid gene transcriptional responses to dietary cholesterol supplementation. As opposed to Mmp9(+/+) (wild-type) mice, Mmp9(-/-) mice failed to decrease the hepatic expression of sterol regulatory element binding protein 2 pathway genes, which control hepatic cholesterol biosynthesis and uptake...
September 30, 2016: Journal of the American Heart Association
Jian-Fei Pei, Yun-Fei Yan, Xiaoqiang Tang, Yang Zhang, Shen-Shen Cui, Zhu-Qin Zhang, Hou-Zao Chen, De-Pei Liu
Cardiac hypertrophy is the strongest predictor of the development of heart failure, and anti-hypertrophic treatment holds the key to improving the clinical syndrome and increasing the survival rates for heart failure. The paraoxonase (PON) gene cluster (PC) protects against atherosclerosis and coronary artery diseases. However, the role of PC in the heart is largely unknown. To evaluate the roles of PC in cardiac hypertrophy, transgenic mice carrying the intact human PON1, PON2, and PON3 genes and their flanking sequences were studied...
August 30, 2016: Science China. Life Sciences
Shih-Hung Tsai, Po-Hsun Huang, Yu-Juei Hsu, Yi-Jen Peng, Chien-Hsing Lee, Jen-Chun Wang, Jaw-Wen Chen, Shing-Jong Lin
Hypoxia inducible factor-1α (HIF-1α) pathway is associated with many vascular diseases, including atherosclerosis, arterial aneurysms, pulmonary hypertension and chronic venous diseases. Significant HIF-1α expression could be found at the rupture edge at human abdominal aortic aneurysm (AAA) tissues. While our initial in vitro experiments had shown that deferoxamine (DFO) could attenuate angiotensin II (AngII) induced endothelial activations; we unexpectedly found that DFO augmented the severity of AngII-induced AAA, at least partly through increased accumulation of HIF-1α...
2016: Scientific Reports
Ingrid Gomez, Gulsev Ozen, Catherine Deschildre, Yasmine Amgoud, Lilia Boubaya, Isabelle Gorenne, Chabha Benyahia, Thomas Roger, Guy Lesèche, Erwan Galardon, Gokce Topal, Marie-Paule Jacob, Dan Longrois, Xavier Norel
Hydrogen sulfide (H2S) is a mediator with demonstrated protective effects for the cardiovascular system. On the other hand, prostaglandin (PG)E2 is involved in vascular wall remodeling by regulating matrix metalloproteinase (MMP) activities. We tested the hypothesis that endogenous H2S may modulate PGE2, MMP-1 activity and endogenous tissue inhibitors of MMPs (TIMP-1/-2). This regulatory pathway could be involved in thinning of abdominal aortic aneurysm (AAA) and thickening of saphenous vein (SV) varicosities...
2016: PloS One
Mehmet Zuhuri Arun, Buket Reel, Graciela B Sala-Newby, Mark Bond, Aikaterini Tsaousi, Perry Maskell, Andrew C Newby
BACKGROUND: Bisphosphonates, including zoledronate, target osteoclasts and are widely used in the treatment of osteoporosis and other bone resorption diseases, despite side effects that include damaging the stomach epithelium. Beneficial and adverse effects on other organ systems, including the cardiovascular system, have also been described and could impact on the use of bisphosphonates as therapeutic agents. Vascular smooth muscle cells (VSMCs) are major constituents of the normal vascular wall and have a key role in intimal thickening and atherosclerosis, in part by secreting MMPs that remodel the extracellular matrix and cleave cell surface proteins or secreted mediators...
2016: Drug Design, Development and Therapy
Andreas Kousios, Panayiotis Kouis, Andrie G Panayiotou
Background. Cardiovascular disease (CVD) remains a significant problem in Chronic Kidney Disease (CKD). Subclinical atherosclerosis identified by noninvasive methods could improve CVD risk prediction in CKD but these methods are often unavailable. We therefore systematically reviewed whether circulating levels of Matrix Metalloproteinases (MMPs) and tissue inhibitors (TIMPs) are associated with subclinical atherosclerosis in CKD, as this would support their use as biomarkers or pharmacologic targets. Methods...
2016: International Journal of Nephrology
Keshav Raj Paudel, Ung-Won Lee, Dong-Wook Kim
OBJECTIVE: Hypercholesterolemia is one of the well-established risk factors for cardiovascular mortality and morbidity in coronary heart disease. The aim of this study was to investigate the anti-atherogenic effect of Chungtaejeon (CTJ, a Korean fermented tea) aqueous extract on proliferation and migration of human aortic smooth muscle cells (HASMCs) in vivo and in vitro. METHODS: The authors used high-fat atherogenic diet (HFAD) to induce hyperlipidemia in Wistar rats in in vivo animal experiments and used HASMCs for in vitro cell experiments...
March 2016: Journal of Integrative Medicine
Liping Meng, Longbin Liu, Changzuan Zhou, Sunlei Pan, Xiaoya Zhai, Chengjian Jiang, Yan Guo, Zheng Ji, Jufang Chi, Fang Peng, Hangyuan Guo
The beneficial effect of Chinese rice wine on atherosclerosis has been proved, but the exact components that have the cardiovascular protective effect are still unknown. This study aimed to explore the exact ingredients in Chinese rice wine that could inhibit homocysteine (Hcy)-induced vascular smooth muscle cell (VSMC) proliferation and migration. VSMCs were divided into 7 groups: control, Hcy (1 mmol/L), Hcy + oligosaccharide, Hcy + polypeptides, Hcy + polyphenols, Hcy + alcohol, and Hcy + Chinese rice wine...
June 2016: Journal of Cardiovascular Pharmacology
Honglin Niu, Ying Li, Haibin Li, Yanqing Chi, Minghui Zhuang, Tao Zhang, Maodong Liu, Lei Nie
Obesity-induced kidney injury contributes to albuminuria, which is characterized by a progressive decline in renal function leading to glomerulosclerosis and renal fibrosis. Matrix metalloproteinases (MMPs) modulate inflammation and fibrosis by degrading a variety of extracellular matrix and regulating the activities of effector proteins. Abnormal regulation of MMP-12 expression has been implicated in abdominal aortic aneurysm, atherosclerosis, and emphysema, but the underlying mechanisms remain unclear. The present study examined the function of MMP-12 in glomerular fibrogenesis and inflammation using apo E(-/-) or apo E(-/-)MMP-12(-/-) mice and maintained on a high-fat-diet (HFD) for 3, 6, or 9 months...
2016: Scientific Reports
Matthew Amin, Sathnur Pushpakumar, Nino Muradashvili, Sourav Kundu, Suresh C Tyagi, Utpal Sen
Matrix metalloproteinases (MMPs) are a family of zinc dependent endopeptidases whose main function is to degrade and deposit structural proteins within the extracellular matrix (ECM). A dysregulation of MMPs is linked to vascular diseases. MMPs are classified into collagenases, gelatinases, membrane-type, metalloelastase, stromelysins, matrilysins, enamelysins, and unclassified subgroups. The production of MMPs is stimulated by factors such as oxidative stress, growth factors and inflammation which lead to its up- or down-regulation with subsequent ECM remodeling...
2016: Frontiers in Bioscience (Landmark Edition)
Karina Di Gregoli, Sarah J George, Christopher L Jackson, Andrew C Newby, Jason L Johnson
AIMS: MMPs contribute to atherosclerotic plaque progression and instability, but the relative potency of their endogenous tissue inhibitors of metalloproteinases (TIMPs) as protective factors has not been defined. We therefore investigated the impact of TIMP-1 and TIMP-2 knockout on atherosclerotic plaque burden and composition in apolipoprotein E-knockout (Apoe(-/-)) mice and studied the underlying effects on monocyte/macrophage behaviour. METHODS AND RESULTS: Analysis of brachiocephalic artery plaques revealed comparable atherosclerotic lesion areas between TIMP-1(-/-) Apoe(-/-) or TIMP-2(-/-) Apoe(-/-) double deficient mice and relevant age-matched, strain-matched Apoe(-/-) controls after 8 weeks of high-fat feeding...
February 1, 2016: Cardiovascular Research
Noemi Cifani, Maria Proietta, Luigi Tritapepe, Cira Di Gioia, Livia Ferri, Maurizio Taurino, Flavia Del Porto
Acute aortic dissection (AAD) is a life-threatening disease with an incidence of about 2.6-3.6 cases per 100,000/year. Depending on the site of rupture, AAD is classified as Stanford-A when the ascending aortic thoracic tract and/or the arch are involved, and Stanford-B when the descending thoracic aorta and/or aortic abdominal tract are targeted. It was recently shown that inflammatory pathways underlie aortic rupture in both type A and type B Stanford AAD. An immune infiltrate has been found within the middle and outer tunics of dissected aortic specimens...
2015: Annals of Medicine
Kinga Buraczynska, Jacek Kurzepa, Andrzej Ksiazek, Monika Buraczynska, Konrad Rejdak
Matrix metalloproteinases (MMPs), endopeptidases degrading extracellular matrix, play an important role in the pathogenesis of atherosclerosis and vascular disease. The aim of this study was to evaluate the association between the C(-1562)T functional polymorphism in the MMP-9 gene and risk of stroke. We examined 322 patients with stroke and 410 controls. In the patient group, 52 % had type 2 diabetes. All subjects were genotyped for the C(-1562)T polymorphism by polymerase chain reaction and restriction analysis...
December 2015: Neuromolecular Medicine
Maged Abdelnaseer, Nervana Elfayomi, Eman H Esmail, Manal M Kamal, Ahmed Hamdy, Rasha M Abdel Samie, Enji Elsawy
Atherosclerosis causes significant morbidity and mortality. Carotid intima media thickness (IMT) predicts future ischaemic strok e incidence. Matrix metalloproteinases (MMPs) play a considerable role in atherosclerosis and hold therapeutic promise as well. To investigate the relationship between serum level of matrix metalloproteinase-9 (MMP-9) and common carotid artery intima media thickness (CCA-IMT) in patients with ischaemic stroke and asymptomatic subjects. Thirty patients with a previous ischaemic stroke and 30 asymptomatic volunteers were recruited...
January 2016: Neurological Sciences
Velidi H Rao, Vikrant Rai, Samantha Stoupa, Devendra K Agrawal
Although degradation of extracellular matrix by matrix metalloproteinases (MMPs) is thought to be involved in symptomatic (S) carotid plaques in atherosclerosis, the mechanisms of MMP expression are poorly understood. Here, we demonstrate that collagen loss in vascular smooth vessel cells (VSMCs) isolated from S plaques was induced by epidermal growth factor (EGF) through the activation of p38-MAPK and JNK-MAPK pathways. Inhibitors of p38-MAPK and JNK-MAPK signaling pathways downregulated the expression of MMP-1 and MMP-9...
September 15, 2015: American Journal of Physiology. Heart and Circulatory Physiology
Ku-Chung Chen, Yi-Chu Liao, Jaw-Yuan Wang, Ying-Chu Lin, Chung-Ho Chen, Suh-Hang Hank Juo
Hyperlipidemia, including the oxidized low-density lipoprotein (oxLDL) accumulation, is a risk and highly associated with the development of cancers and cardiovascular diseases. microRNA-210 (miR-210), a hypoxia-responsive microRNA regulated by HIF-1α, has been implicated in cancer and cardiovascular disease formation. Furthermore, Bioinformatics analysis revealed that the promoter of the miR-210 gene contains CpG-rich regions. It is unclear whether miR-210 expression could be epigenetically regulated in these disease progresses...
September 15, 2015: Oncotarget
E Hopps, G Caimi
OBJECTIVE: Matrix metalloproteases (MMPs) are involved in the development and the progression of atherosclerosis and are related to an elevated risk of cardiovascular morbidity and mortality. An altered profile of MMPs and their tissue inhibitors (TIMPs) has been demonstrated in arterial hypertension, diabetes mellitus, obesity, metabolic syndrome and in cardiovascular disorders, such as coronary artery disease, atrial fibrillation, and heart failure. MATERIALS AND METHODS: The aim of this review was to examine the literature data regarding the possible effects of some molecules, commonly employed in subjects with cardiovascular disease, on the expression and the activity of MMPs and TIMPs...
2015: European Review for Medical and Pharmacological Sciences
R B Kostogrys, C Johann, I Czyżyńska, M Franczyk-Żarów, A Drahun, E Maślak, A Jasztal, M Gajda, Ł Mateuszuk, T P Wrobel, M Baranska, I Wybrańska, K Jezkova, P Nachtigal, S Chlopicki
INTRODUCTION: Low Carbohydrate High Protein diet represents a popular strategy to achieve weight loss. OBJECTIVE: The aim of this study was to characterize effects of low carbohydrate, high protein diet (LCHP) on atherosclerotic plaque development in brachiocephalic artery (BCA) in apoE/LDLR-/- mice and to elucidate mechanisms of proatherogenic effects of LCHP diet. MATERIALS AND METHODS: Atherosclerosis plaques in brachiocephalic artery (BCA) as well as in aortic roots, lipoprotein profile, inflammation biomarkers, expression of SREBP-1 in the liver as well as mortality were analyzed in Control diet (AIN-93G) or LCHP (Low Carbohydrate High Protein) diet fed mice...
August 2015: Journal of Nutrition, Health & Aging
Monika Buraczynska, Michal Dragan, Kinga Buraczynska, Grazyna Orlowska-Kowalik, Andrzej Ksiazek
OBJECTIVE: Matrix metalloproteinases (MMPs) play an important role in pathogenesis of atherosclerosis and vascular disease. We hypothesized that MMP-2 might be a susceptibility gene for cardiovascular disease (CVD) in diabetes. The aim of this study was to evaluate the association between C(-1306)T functional polymorphism in the MMP-2 gene and risk of CVD in type 2 diabetes patients. METHODS: We examined 1090 patients with T2DM and 612 controls. All subjects were genotyped for the C(-1306)T polymorphism by polymerase chain reaction (PCR) and restriction analysis...
August 2015: Journal of Diabetes and its Complications
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