Background Oxidative stress and inflammation are important steps in the pathogenesis of atherosclerosis. We postulated that therapeutic concentrations of aspirin and pravastatin, especially in combination, may suppres...Background Oxidative stress and inflammation are important steps in the pathogenesis of atherosclerosis. We postulated that therapeutic concentrations of aspirin and pravastatin, especially in combination, may suppress oxidative stress and inflammation in endothelial cells, and this concept was examined in human coronary artery endothelial cells （HCAECs）. Methods Human coronary artery endothelial cells were cultured and treated with oxidized-low density lipoprotein （ox-LDL, 60 ug/ml for 24 hours） alone, or pre-treated with aspirin （1, 2 or 5 mmol/L）, pravastatin （1, 5 or 10 umol/L） or their combination （1 mmol/L aspirin and 5umol/L pravastatin）, followed by ox-LDL treatment. After respective treatment, superoxide anion production, p38 mitogen activated protein kinase and transcription factor NF-KB activation, protein expression of lectin-like ox-LDL receptor-1 （LOX-1） and adhesion molecules, and monocyte adhesion were measured. Results Ox-LDL treatment greatly elicited its receptor LOX-1 expression, superoxide anion production and inflammatory response, which were minimally affected by low concentration of aspirin （1 mmol/L） or pravastatin （5umol/L）, but were markedly decreased by their combination. Activation of p38 mitogen activated protein kinase and NF-KB, the expression of intercellular adhesion molecule-1 and monocyte chemotactic protein-I, which were only mildly affected by aspirin or pravastatin alone, were significantly attenuated by their combination. As a consequence, monocyte adhesion to endothelial cells was markedly attenuated by the combination of the two agents. Well-known anti-oxidants a-tocopherol and y-tocopherol had similar inhibitory effects on ox-LDL-mediated oxidative stress and LOX-1 expression as well as monocyte adhesion as did the combination of aspirin and pravastatin. Conclusions These studies point to a positive interaction between aspirin and pravastatin with regard to endothelial bioloqy. Anti-oxidant and subsequent anti-inflammatory effect may be on展开更多
Statins [(3-hydroxy-3-methylglutaryl-coenzyme A reductase, HMG-CoA reductase, abbreviated HMGCR) inhibitors] inhibit cholesterol synthesis and are commonly used in the treatment and prevention of cardiovascular diseas...Statins [(3-hydroxy-3-methylglutaryl-coenzyme A reductase, HMG-CoA reductase, abbreviated HMGCR) inhibitors] inhibit cholesterol synthesis and are commonly used in the treatment and prevention of cardiovascular diseases. Preclinical and clinical studies have shown that the drug can be effective in several cancers including breast cancer which is the second most frequent cancer in the world and the commonest one among women. In breast cancer cell lines statins reduce proliferation, increase apoptosis, decrease invasion and sensitize them to radiation. Clinical trials in breast cancer patients have shown positive outcome in terms of decreased recurrence rate, decreased mortality and positive role as neoadjuvant agent. They may have a particular role in treatment-resistant cases like triple-negative or inflammatory breast cancer which have a poorer prognosis. There is also evidence of their potential use in metastatic bone disease from breast cancer. When statins inhibit 3-hydroxy-3-methylgutaryl CoA reductase which is the rate-limiting enzyme of the mevalonate pathway, the levels of mevalonate as well as its downstream products are decreased. Hence cancer growth is inhibited by reduced prenylation of CAAX proteins, N-Glycosylation of growth factor receptors and synthesis of membrane and steroid among others. Also statins are relatively cheap and can contribute to decrease the high cost of cancer treatment. However studies till now have not shown any association with decreased breast cancer incidence. In addition there are doubts regarding safety of statins when used over a prolonged period of time. Although statins are relatively safe with myotoxicity and hepatotoxicity being their major side effects, evidence regarding issues like drug interactions with anti-cancer drugs is lacking.展开更多
文摘Background Oxidative stress and inflammation are important steps in the pathogenesis of atherosclerosis. We postulated that therapeutic concentrations of aspirin and pravastatin, especially in combination, may suppress oxidative stress and inflammation in endothelial cells, and this concept was examined in human coronary artery endothelial cells （HCAECs）. Methods Human coronary artery endothelial cells were cultured and treated with oxidized-low density lipoprotein （ox-LDL, 60 ug/ml for 24 hours） alone, or pre-treated with aspirin （1, 2 or 5 mmol/L）, pravastatin （1, 5 or 10 umol/L） or their combination （1 mmol/L aspirin and 5umol/L pravastatin）, followed by ox-LDL treatment. After respective treatment, superoxide anion production, p38 mitogen activated protein kinase and transcription factor NF-KB activation, protein expression of lectin-like ox-LDL receptor-1 （LOX-1） and adhesion molecules, and monocyte adhesion were measured. Results Ox-LDL treatment greatly elicited its receptor LOX-1 expression, superoxide anion production and inflammatory response, which were minimally affected by low concentration of aspirin （1 mmol/L） or pravastatin （5umol/L）, but were markedly decreased by their combination. Activation of p38 mitogen activated protein kinase and NF-KB, the expression of intercellular adhesion molecule-1 and monocyte chemotactic protein-I, which were only mildly affected by aspirin or pravastatin alone, were significantly attenuated by their combination. As a consequence, monocyte adhesion to endothelial cells was markedly attenuated by the combination of the two agents. Well-known anti-oxidants a-tocopherol and y-tocopherol had similar inhibitory effects on ox-LDL-mediated oxidative stress and LOX-1 expression as well as monocyte adhesion as did the combination of aspirin and pravastatin. Conclusions These studies point to a positive interaction between aspirin and pravastatin with regard to endothelial bioloqy. Anti-oxidant and subsequent anti-inflammatory effect may be on
文摘Statins [(3-hydroxy-3-methylglutaryl-coenzyme A reductase, HMG-CoA reductase, abbreviated HMGCR) inhibitors] inhibit cholesterol synthesis and are commonly used in the treatment and prevention of cardiovascular diseases. Preclinical and clinical studies have shown that the drug can be effective in several cancers including breast cancer which is the second most frequent cancer in the world and the commonest one among women. In breast cancer cell lines statins reduce proliferation, increase apoptosis, decrease invasion and sensitize them to radiation. Clinical trials in breast cancer patients have shown positive outcome in terms of decreased recurrence rate, decreased mortality and positive role as neoadjuvant agent. They may have a particular role in treatment-resistant cases like triple-negative or inflammatory breast cancer which have a poorer prognosis. There is also evidence of their potential use in metastatic bone disease from breast cancer. When statins inhibit 3-hydroxy-3-methylgutaryl CoA reductase which is the rate-limiting enzyme of the mevalonate pathway, the levels of mevalonate as well as its downstream products are decreased. Hence cancer growth is inhibited by reduced prenylation of CAAX proteins, N-Glycosylation of growth factor receptors and synthesis of membrane and steroid among others. Also statins are relatively cheap and can contribute to decrease the high cost of cancer treatment. However studies till now have not shown any association with decreased breast cancer incidence. In addition there are doubts regarding safety of statins when used over a prolonged period of time. Although statins are relatively safe with myotoxicity and hepatotoxicity being their major side effects, evidence regarding issues like drug interactions with anti-cancer drugs is lacking.
