MAPK pathway activation by chronic lead-exposure increases vascular reactivity through oxidative stress/cyclooxygenase-2-dependent pathways

Abstract

Chronic exposure to low lead concentration produces hypertension; however, the underlying mechanisms remain unclear. We analyzed the role of oxidative stress, cyclooxygenase-2-dependent pathways and MAPK in the vascular alterations induced by chronic lead exposure. Aortas from lead-treated Wistar rats (1st dose: 10 μg/100g; subsequent doses: 0.125μg/100g, intramuscular, 30days) and cultured aortic vascular smooth muscle cells (VSMCs) from Sprague Dawley rats stimulated with lead (20μg/dL) were used. Lead blood levels of treated rats attained 21.7±2.38μg/dL. Lead exposure increased systolic blood pressure and aortic ring contractile response to phenylephrine, reduced acetylcholine-induced relaxation and did not affect sodium nitroprusside relaxation. Endothelium removal and L-NAME left-shifted the response to phenylephrine more in untreated than in lead-treated rats. Apocynin and indomethacin decreased more the response to phenylephrine in treated than in untreated rats. Aortic protein expression of gp91(phox), Cu/Zn-SOD, Mn-SOD and COX-2 increased after lead exposure. In cultured VSMCs lead 1) increased superoxide anion production, NADPH oxidase activity and gene and/or protein levels of NOX-1, NOX-4, Mn-SOD, EC-SOD and COX-2 and 2) activated ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized superoxide anion production, NADPH oxidase activity and mRNA levels of NOX-1, NOX-4 and COX-2. Blockade of the ERK1/2 and p38 signaling pathways abolished lead-induced NOX-1, NOX-4 and COX-2 expression. Results show that lead activation of the MAPK signaling pathways activates inflammatory proteins such as NADPH oxidase and COX-2, suggesting a reciprocal interplay and contribution to vascular dysfunction as an underlying mechanisms for lead-induced hypertension.

Low-level Chronic Lead Exposure Impairs Neural Control of Blood Pressure and Heart Rate in Rats

“…We recently demonstrated that chronic lead acetate administration in rats, leading to blood concentrations as low as 10-20 lg/dL, elevates BP and increases vascular reactivity [7][8][9]. These results reinforce the idea of hazardous lead effects even at low levels.…”

“…Of the probable mechanisms involved in the genesis and maintenance of BP elevations induced by lead exposure, numerous studies point to increased peripheral vascular resistance due to endothelial [9,10,29] and vascular smooth muscle dysfunction [9], increased endothelin [11], oxidative stress [9,10,12,29] and reduced NO bioavailability [12,29]. Moreover, activation of the renin-angiotensin system, which is closely associated with ANS activation, would also be present in acute and chronic lead toxicities [13,39].…”

Age‐dependent alterations to paraventricular nucleus insulin‐like growth factor 1 receptor as a possible link between sympathoexcitation and inflammation

“…; Simões et al . ). As a result, nNOS and other antioxidant (induced nitric oxide synthase and Cyclooxygenase) systems are depleted leading to an increase in inflammation through oxidative stress (Zhang et al .…”

“…MAPK/ErK increases JNK and cJUN which promotes nuclear activation and post-translational modifications of HMGB1 (Chen et al 2012a,b;Dange et al 2015). In addition, previous studies have shown that an increase in MAPK/ErK is associated with up-regulated NADPH oxidase and oxidative stress (Morales et al 2014;Simões et al 2015). As a result, nNOS and other antioxidant (induced nitric oxide synthase and Cyclooxygenase) systems are depleted leading to an increase in inflammation through oxidative stress (Zhang et al 1998;DiCarlo et al 2002;Dai et al 2014).…”

Treatment with high dose of atorvastatin reduces vascular injury in diabetic rats

“…Proteins from homogenized arteries were quantified as previously described [22]. Were used mouse monoclonal antibodies anti-COX-2 (1:200; Cayman Chemical, MI, USA) or anti-NADPH subunit NOX1 (gp 22phox , 1:1000; Transduction Laboratories, Lexington, UK), and anti-mouse immunoglobulin antibody conjugated to horseradish peroxidase (1:5000; StressGen, Victoria, Canada).…”