Biomedical subjects

R D Natarajan

Publications and source records attributed to R D Natarajan.

6 recordsLinked to original sources

PubMed1999

12-Lipoxygenase products increase monocyte:endothelial interactions.

In summary, we suggest that hyperglycemia causes upregulation of 12-lipoxygenase activity. The increased production of 12-LO products, 12(S) and 15(S)-HETE, activates monocyte integrins which result in enhanced adhesion of monocytes to endothelium. The binding of monocytes to endothelium is a key early event in development of atherosclerosis. Upregulation of this process by vascular cells exposed to chronic elevations in glucose may be one explanation for the accelerated atherosclerosis observed in patients with Type 2 diabetes.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed1994

Evidence that glucose increases monocyte binding to human aortic endothelial cells.

The rate of atherosclerosis is accelerated in humans with diabetes. The adhesion of monocytes to the vascular endothelium is a key event in the development of atherosclerosis. Alloxan (ALX)-induced diabetes in rabbits causes leukocyte accumulation on the arterial surface. However, the effect of glucose exposure on monocyte binding is not understood. We evaluated the effect of chronic elevated glucose on human monocyte binding to human aortic endothelial cells (HAEC) in culture. Monocyte binding to HAEC was significantly increased by chronic incubation of HAEC in high glucose for 7-10 days (CH-HG; 25 mM) compared with cells cultured for the same time in normal glucose (5.5 mM; CH-HG, 188 +/- 10 cells/field vs. normal glucose, 111 +/- 7; P < 0.0005). Use of mannitol at a concentration to stimulate the hyperosmolar effects of glucose did not significantly alter monocyte binding. Acute 20-min exposure of HAEC to high glucose did not alter monocyte binding. The adherence of HL-60 cells, a neutrophil-like cell line, or human neutrophils was not induced by CH-HG culture. High glucose-induced monocyte binding was not associated with induction of the major endothelial cell adhesion molecules, including E-selectin, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1 (ICAM-1). A monoclonal antibody TS1-18 to the beta 2 integrin component that is involved in binding to ICAM-1 on endothelial cells significantly reduced monocyte binding, whereas anti-VLA-4 antibody was not effective. These results suggest that hyperglycemia can accelerate the rate of atherosclerosis in diabetics by increasing monocyte binding to the endothelium.

Analysis of Variance↗

PubMed1992

Gonadotropin releasing hormone activates the lipoxygenase pathway in cultured pituitary cells: role in gonadotropin secretion and evidence for a novel autocrine/paracrine loop.

The formation and role of arachidonic acid (AA) and its metabolites during gonadotropin releasing hormone- (GnRH-) induced gonadotropin secretion were investigated in primary cultures of rat pituitary cells. Prelabeled cells ([3H]AA) responded to GnRH challenge with increased formation (about 2-fold) of the leukotrienes LTC4, LTD4, and LTE4 as well as 5- and 15-eicosatetraenoic acids (5- and 15-HETE) as identified by HPLC. Formation of leukotrienes and 15-HETE was further verified by specific radioimmunoassays. No significant increase in the formation of 12-HETE or of the cyclooxygenase products prostaglandin E (PGE) and thromboxane A2 by GnRH was noticed. Addition of physiological concentrations of LTC4 enhanced basal LH release, while subphysiological concentrations of LTC4 (10(-15)-10(-12) M) inhibited GnRH-induced LH release by about 35% (p less than 0.02). Using specific lipoxygenase inhibitors L-656,224 and MK 886, we found inhibition of GnRH-induced LH release by about 40% at concentrations known to specifically inhibit the 5-lipoxygenase pathway. The peptidoleukotriene receptor antagonist ICI 198,615 inhibited LTC4- and LTE4-induced LH release and surprisingly also the effect of GnRH on LH release by 40%. The data strongly suggest a role for AA and its lipoxygenase metabolites in the on/off reactions of GnRH upon LH release. The data also present a novel amplification cycle in which newly formed leukotrienes become first messengers and establish an autocrine/paracrine loop.

Animals↗

PubMed1992

Intracellular free magnesium deficiency plays a key role in increased platelet reactivity in type II diabetes mellitus.

OBJECTIVE: Mg deficiency may be an important factor leading to cardiovascular disease. Diabetic subjects show an increase in platelet reactivity that can enhance the risks of vascular disease. In addition, diabetic patients have been reported to be at risk of developing extracellular Mg deficiency. However, the intracellular free Mg concentration and its role in the enhanced platelet reactivity in diabetes is not known. RESEARCH DESIGN AND METHODS: We evaluated the intracellular erythrocyte (RBC) Mg2+ concentration in 20 non-insulin-dependent (type II) diabetics. In addition, the effects of intravenous 3-h drip or 8 wk of oral Mg supplementation on intracellular RBC Mg2+ levels and platelet reactivity was studied. To more clearly evaluate the direct role of Mg in these effects, we induced isolated Mg deficiency in 16 nondiabetic control subjects with an Mg-free liquid diet for 3 wk. RESULTS: The intracellular RBC Mg2+ concentration of diabetic patients was significantly reduced compared with values in nondiabetic control subjects (166 +/- 7 vs. 204 +/- 7 microM, P less than 0.01). Serum Mg levels were also reduced in the diabetic patients compared with the control subjects (1.59 +/- 0.04 vs. 1.9 +/- 0.1 mEq/L, P less than 0.05). Oral Mg supplementation for 8 wk (400 mg/day) restored RBC Mg2+ concentration to normal without significantly changing serum Mg concentration. Both intravenous and oral Mg supplementation markedly reduced platelet reactivity in response to the thromboxane A2 analog, U46619. The Mg-free diet resulted in a significant reduction in RBC Mg2+ concentration and markedly enhanced the sensitivity of platelet aggregation to U46619 and ADP. CONCLUSIONS: These results suggest that type II diabetic patients have intracellular Mg2+ deficiency and that Mg deficiency may be a key factor in leading to enhanced platelet reactivity in type II diabetes. Therefore, Mg supplementation may provide a new therapeutic approach to reducing vascular disease in patients with diabetes.

Adult↗

PubMed1987

The function of NADH-semidehydroascorbate reductase and ascorbic acid in corticosteroid hydroxylation.

We have demonstrated in rat adrenal (Natarajan, R.D. and Harding, B.W. (1985) J. Biol. Chem. 260, 3902-3905) that NADH-semidehydroascorbate reductase and ascorbate participate in an electron transport pathway (ETP) supplying reducing equivalents from NADH to cytochrome P-450scc. Here, we demonstrate that this ascorbate dependent ETP also supplies reducing equivalents to cytochrome P-450(11 beta/18) in both rat adrenal and bovine adrenal cortex. The activity is dependent upon addition of catalase or upon 'cold shock' treatment of isolated mitochondria. Comparison of the rates of 11 beta- and 18-hydroxylation supported by this ETP and by the classical pathway supported by various TCA cycle intermediates suggests that in vivo the ascorbate dependent pathway may be essential for maximal flow of reducing equivalents to the mitochondrial hydroxylases. Partial reconstitution of the ascorbate dependent 11 beta/18-hydroxylase activity was achieved with purified bovine outer mitochondrial and inner mitochondrial membranes fortified with supernatant from sonified mitochondria all preincubated with phosphatidyl choline. These preparations no longer require catalase or 'cold shock' treatment. Ascorbate and NADH-semidehydroascorbate reductase are unable to support 17 alpha- or 21-hydroxylase activity in isolated bovine adrenal cortical microsomes whether incubated with purified outer mitochondrial membranes or not.

Adrenal Cortex↗

PubMed1985

Cholesterol side chain cleavage in rat adrenal supported by outer mitochondrial membrane NADH-semidehydroascorbate reductase.

Rat adrenal mitochondria have an active rotenone-insensitive outer mitochondrial membrane NADH-semidehydroascorbate (NADH-SDA) reductase which supports cholesterol side chain cleavage at a rate equal to that supported by malate. Side chain cleavage activity supported by both of these electron donor systems is equally inhibited by cycloheximide. Catalase or butylated hydroxyanisole are required for the NADH-SDA reductase-supported cholesterol side chain cleavage. This requirement can be removed by briefly subjecting the mitochondrial preparations to -20 degrees C. Ascorbic acid alone or with malate is either inhibitory or has no effect on side chain cleavage activity. These observations demonstrate that outer mitochondrial membrane NADH-SDA reductase in rat adrenal functions to provide cytoplasmic reducing equivalents to intramitochondrial cytochrome P-450scc and provides a new explanation for the function of ascorbic acid in corticosteroidogenesis.

Adrenal Glands↗