Nifedipine Activates PPARγ and Exerts Antioxidative Action Through Cu/ZnSOD Independent of Blood-pressure Lowering in SHRSP

Abstract

Aim:It has been shown that the calcium antagonist nifedipine upregulates superoxide dismutase (SOD). Although the peroxisome proliferator-activated receptor (PPAR) response element is located in the promoter region of Cu/ZnSOD, it remains unclear whether nifedipine upregulates PPARs and inhibits vascular remodeling. We hypothesthized that nifedipine activates PPAR , inhibits vascular remodeling, and improves vascular function in hypertension. Methods: Stroke-prone spontaneously hypertensive rats (SHRSP) were treated with vehicle, nifedipine, and PPAR selective antagonist GW9662 with nifedipine. Results: Systolic blood pressure in the three SHRSP groups was higher ( p 0.01), and the left ventricular weight/body weight ratio was greater ( p 0.01) than in the Wistar-Kyoto rat (WKY) group with no differences observed among the three SHRSP groups. In the SHRSP heart, nifedipine significantly inhibited intramyocardial arterial remodeling and perivascular fibrosis, and reduced oxidative stress, while it significantly restored adiponectin and the smooth muscle cell (SMC) phenotype, and selectively restored PPAR and Cu/ZnSOD expression/activities to their levels in the WKY rat heart.

Angiotensin Ⅱ Activates MCP-1 and Induces Cardiac Hypertrophy and Dysfunction via Toll-like Receptor 4

“…The left ventricles of the hearts were subsequently separated, washed with heparinized saline, weighed and cut into four pieces perpendicular to the long axis. A piece of the middle portion of the heart tissue from each heart was snap frozen with optimal cutting temperature (OCT) compound in liquid nitrogen to obtain fresh frozen, 40-µm-thick sections for dihydroethidium (DHE) staining 24,25) . The other middle portion of the heart, which was fixed in 10% buffered formaldehyde, was embedded in paraffin and sectioned into 4-µm slices for assessments of the expression levels of pNF-κB and MCP-1 and morphology using Masson Trichrome or hematoxylin-eosin (HE) staining.…”

“…The other middle portion of the heart, which was fixed in 10% buffered formaldehyde, was embedded in paraffin and sectioned into 4-µm slices for assessments of the expression levels of pNF-κB and MCP-1 and morphology using Masson Trichrome or hematoxylin-eosin (HE) staining. The rest of the base and apex-side heart tissues were frozen in liquid nitrogen and stored at −80 °C until use in the other experiments 25) .…”

“…The · O 2− content was evaluated using fluorescent DHE 2 µmol/L (Polysciences, Warrington, PA), as previously described 25, 27) . The specificity of DHE signals for · O 2− detection was confirmed via preincubation with superoxide dismutase (SOD)-mimetic Tempol (500 U/mL), and the images were obtained with a laser scanning confocal microscope (LSM510; Zeiss, Munich, Germany).…”

“…The NADPH oxidase activity was determined using a luminescence assay 25) . Briefly, the heart tissues were placed in a chilled, modified Krebs-hydroxyethyl piperazineethanesulfonic acid (HEPES) buffer (99 mmol/L NaCl, 4.7 mmol/L KC1, 1.9 mmol/L CaC1 2 , 1.2 mmol/L MgSO 4 , 1.0 mmol/L K 2 HPO 4 , 25 mmol/L NaHCO3, 20 mmol/L Na-HEPES and 11 mmol/L glucose, pH 7.4), after which a 10% (w/v) tissue homogenate in 50 mmol/L of phosphate buffer was subjected to centrifugation at 1,000 × g for 10 minutes to remove unbroken cells and debris.…”

Mechanisms of antiplatelet activity of nifedipine

“…Therefore, reagents exerting PPAR-activating activity could potentially provide an antiplatelet treatment. Nifedipine can increase the PPAR-g activity in macrophages and smooth muscle cells (SMCs) [15,16], suggesting that its effects might thus be associated with PPARs. To date, no previous study has investigated the possible contribution of PPARs to nifedipine-mediated antiplatelet activity.…”