Publications (9) View all
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Article: Hypomorphic Sialidase expression decreases serum cholesterol by downregulationof VLDL production in Mice.
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ABSTRACT: Lipoprotein metabolism is an important contributing factor in the development and progression of atherosclerosis. Plasma lipoproteins and their receptors are heavily glycosylated and sialylated, and levels of sialic acids modulate their biological functions. Sialylation is controlled by the activities of sialyltranferases and sialidases. In order to address the impact of sialidase (neu1) activity on lipoprotein metabolism, we have generated a mouse model with a hypomorphic neu1 allele (B6.SM) that displays reduced sialidase expression and sialidase activity. The objectives of this study are to determine the impact of sialidase on the rate of hepatic lipoprotein secretion, and lipoprotein uptake. Our results indicate that hepatic levels of cholesterol and triglycerides are significantly higher in B6.SM mice compared to C57Bl/6 mice; however, VLDL-triglyceride production rate is lower. In addition, B6SM mice show significantly lower levels of hepatic MTP and active SREBP-2 but higher levels of DGAT2; these are all indicative of increased hepatic lipid storage. Rescue of sialidase activity in hypomorphic sialidase mice using helper dependent adenovirus resulted in increased VLDL production and an increase in MTP levels. Furthermore, hypomorphic sialidase expression results in stabilization of hepatic LDLR protein expression, which enhances LDL uptake. These findings provide novel evidence for a central role of sialidase in the cross talk between the uptake and production of lipoproteins.The Journal of Lipid Research 09/2012; · 5.56 Impact Factor -
Article: The effect of pomegranate extract on coronary artery atherosclerosis in SR-BI/APOE double knockout mice.
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ABSTRACT: OBJECTIVES: To examine the effects of pomegranate extract on inflammation and oxidative stress and the development of spontaneous occlusive coronary artery atherosclerosis in the SR-BI/apoE double knockout mouse model of coronary heart disease. METHODS AND RESULTS: SR-BI/apoE double KO mice were treated for two weeks with pomegranate extract via drinking water, beginning at three weeks of age. Treatment with pomegranate extract increased cholesterol ester content and reduced the abnormally high unesterified/esterified cholesterol ratio of VLDL-sized lipoproteins. Despite the increase in cholesterol levels associated with VLDL-sized particles, pomegranate extract treatment reduced the size of atherosclerotic plaques in the aortic sinus and reduced the proportion of coronary arteries with occlusive atherosclerotic plaques. Treatment with pomegranate extract resulted in substantial reductions in levels of oxidative stress and monocyte chemotactic protein-1 in atherosclerotic plaques in the aortic sinus and coronary arteries. In addition, treatment with pomegranate extract reduced lipid accumulation, macrophage infiltration, levels of monocyte chemotactic protein-1 and fibrosis in the myocardium, attenuated cardiac enlargement and the development of ECG abnormalities in SR-BI/apoE double KO mice. CONCLUSION: Pomegranate extract reduced aortic sinus and coronary artery atherosclerosis in SR-BI/apoE dKO mice. The atheroprotective effects of pomegranate extract appear to involve reduced oxidative stress and inflammation in the vessel wall despite unaltered systemic markers of inflammation and increased lipoprotein cholesterol in these mice.Atherosclerosis 03/2013; · 3.79 Impact Factor -
Article: On the origin of rhythmic calcium transients in the ICC-MP of the mouse small intestine.
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ABSTRACT: Interstitial cells of Cajal associated with the myenteric plexus (ICC-MP) are pacemaker cells of the small intestine, producing the characteristic omnipresent electrical slow waves, which orchestrate peristaltic motor activity and are associated with rhythmic intracellular calcium oscillations. Our objective was to elucidate the origins of the calcium transients. We hypothesized that calcium oscillations in the ICC-MP are primarily regulated by the sarcoplasmic reticulum (SR) calcium release system. With the use of calcium imaging, study of the effect of T-type calcium channel blocker mibefradil revealed that T-type channels did not play a major role in generating the calcium transients. 2-Aminoethoxydiphenyl borate, an inositol 1,4,5 trisphosphate receptor (IP(3)R) inhibitor, and U73122, a phospholipase C inhibitor, both drastically decreased the frequency of calcium oscillations, suggesting a major role of IP(3) and IP(3)-induced calcium release from the SR. Immunohistochemistry proved the expression of IP(3)R type I (IP(3)R-I), but not type II (IP(3)R-II) and type III (IP(3)R-III) in ICC-MP, indicating the involvement of the IP(3)R-I subtype in calcium release from the SR. Cyclopiazonic acid, a SR/endoplasmic reticulum calcium ATPase pump inhibitor, strongly reduced or abolished calcium oscillations. The Na-Ca exchanger (NCX) in reverse mode is likely involved in refilling the SR because the NCX inhibitor KB-R7943 markedly reduced the frequency of calcium oscillations. Immunohistochemistry revealed 100% colocalization of NCX and c-Kit in ICC-MP. Testing a mitochondrial NCX inhibitor, we were unable to show an essential role for mitochondria in regulating calcium oscillations in the ICC-MP. In summary, ongoing IP(3) synthesis and IP(3)-induced calcium release from the SR, via the IP(3)R-I, are the major drivers of the calcium transients associated with ICC pacemaker activity. This suggests that a biochemical clock intrinsic to ICC determines the pacemaker frequency, which is likely directly linked to kinetics of the IP(3)-activated SR calcium channel and IP(3) metabolism.AJP Gastrointestinal and Liver Physiology 08/2011; 301(5):G835-45. · 3.43 Impact Factor -
Article: Igf1r+/CD34+ immature ICC are putative adult progenitor cells, identified ultrastructurally as fibroblast‐like ICC in Ws/Ws rat colon
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ABSTRACT: The colon of Ws/Ws mutant rats shows impairment of pacemaker activity and altered inhibitory neurotransmission. The present study set out to find structural correlates to these findings to resolve mechanisms. In the colon of Ws/Ws rats, interstitial cells of Cajal associated with Auerbach’s plexus (ICC-AP) were significantly decreased and ICC located at the submuscular plexus and intramuscular ICC were rarely observed based on immunohistochemistry and electron microscopy. Ultrastructural investigations revealed that there was no overall loss of all types of interstitial cells combined. Where loss of ICC was observed, a marked increase in fibroblast-like ICC (FL-ICC) was found at the level of AP. Immunoelectron microscopy proved FL-ICC to be c-Kit– but gap junction coupled to each other and to c-Kit+ ICC; they were associated with enteric nerves and occupied space normally occupied by ICC in the wild-type rat colon, suggesting them to be immature ICC. In addition, a marked increase in immunoreactivity for insulin-like growth factor 1 receptor (Igf1r) occurred, co-localized with CD34 but not with c-Kit. A significantly higher number of Igf1r+/CD34+ cells were found in Ws/Ws compared to wild-type rat colons. These CD34+/Igf1r+ cells in the Ws/Ws colon occupied the same space as FL-ICC. Hence we propose that a subset of immature ICC (FL-ICC) consists of adult progenitor cells. Immunohistochemistry revealed a reduction of neurons positive for neuronal nitric oxide synthase. The functional capabilities of the immature ICC and the regenerative capabilities of the adult progenitor cells need further study. The morphological features described here show that the loss of pacemaker activity is not associated with failure to develop a network of interstitial cells around AP but a failure to develop this network into fully functional pacemaker cells. The reduction in nitrergic innervation associated with the Ws mutation may be the result of a reduction in nitrergic neurons.Journal of Cellular and Molecular Medicine 08/2009; 13(9b):3528 - 3540. · 4.13 Impact Factor -
Article: Deficiency of intramuscular ICC increases fundic muscle excitability but does not impede nitrergic innervation.
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ABSTRACT: The motility of the gastrointestinal tract is generated by smooth muscle cells and is controlled to a large extent by an intrinsic neural network. A gap of approximately 200 nm usually separates nerve varicosities from smooth muscle cells, which suggests that direct innervation of the smooth muscle by synapses does not occur. Enteric nerves do make synapse-like contact with proposed regulatory cells, the interstitial cells of Cajal (ICC), which in turn may be in gap junction contact with smooth muscle cells. The role played by ICC in enteric innervation is controversial. Experimental evidence has been presented in vitro for the hypothesis that nitrergic inhibitory innervation is strongly reduced in the absence of ICC. However, in vivo data appear to dispute that. The present report provides evidence that explains the discrepancy between in vivo and in vitro data and provides evidence that inhibitory neurotransmitters can reach smooth muscle cells without hindrance when ICC are absent. The fundic musculature shows increased responses to substance P-mediated innervation and shows marked spontaneous activity, which is consistent with increased muscle excitability.AJP Gastrointestinal and Liver Physiology 03/2008; 294(2):G589-94. · 3.43 Impact Factor
