Nifedipine Induces Peroxisome Proliferator-Activated Receptor-γ Activation in Macrophages and Suppresses the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice

Abstract

Objective-Nifedipine, an L-type calcium channel blocker, protects against the progression of atherosclerosis. We investigated the molecular basis of the antiatherosclerotic effect of nifedipine in macrophages and apolipoprotein E-deficient mice. Methods and Results-In macrophages, nifedipine increased peroxisome proliferator-activated receptor-␥ (PPAR␥) activity without increasing PPAR␥-binding activity. Amlodipine, another L-type calcium channel blocker, and 1,2-bis-(oaminophenoxy)-ethane-N,N,-NЈ,NЈ-tetraacetic acid tetraacetoxy-methyl ester (BAPTA-AM), a calcium chelator, decreased PPAR␥ activity, suggesting that nifedipine does not activate PPAR␥ via calcium channel blocker activity. Inactivation of extracellular signal-regulated kinase 1/2 suppressed PPAR␥2-Ser112 phosphorylation and induced PPAR␥ activation. Nifedipine suppressed extracellular signal-regulated kinase 1/2 activation and PPAR␥2-Ser112 phosphorylation, and mutating PPAR␥2-Ser112 to Ala abrogated nifedipine-mediated PPAR␥ activation. These results suggested that nifedipine inhibited extracellular signal-regulated kinase 1/2 activity and PPAR␥2-Ser112 phosphorylation, leading to PPAR␥ activation. Nifedipine inhibited lipopolysaccharide-induced monocyte chemoattractant protein-1 expression and induced ATP-binding cassette transporter A1 mRNA expression, and these effects were abrogated by small interfering RNA for PPAR␥. Furthermore, in apolipoprotein E-deficient mice, nifedipine treatment decreased atherosclerotic lesion size, phosphorylation of PPAR␥2-Ser112 and extracellular signal-regulated kinase 1/2, and monocyte chemoattractant protein-1 mRNA expression and increased ATP-binding cassette transporter A1 expression in the aorta. Key Words: atherosclerosis Ⅲ macrophages Ⅲ hypertension Ⅲ peroxisome proliferator-activated receptor Ⅲ vascular biology H ypertension is a major risk factor for atherosclerosis. 1,2 However, the detailed mechanisms that link elevated blood pressure to progression of atherosclerosis remain unclear. Hypertension may promote the expression of cell adhesion molecules in endothelial cells 3 and production of cytokines in the vessel wall, 4 suggesting that hypertensive stress stimulates a proinflammatory response and contributes to the progression of atherogenesis. On the other hand, low-density lipoprotein (LDL) derived from hypertensive patients is more susceptible to lipid peroxidation mediated by angiotensin II and to its cellular uptake by macrophages than that obtained from normotensive subjects. 5 Therefore, monocyte-derived macrophages and macrophage-derived foam cells may accelerate atherosclerosis in hypertensive patients. Conclusion-NifedipineMassive clustering of macrophage-derived foam cells in the subendothelial spaces of arterial walls is a characteristic feature of early atherosclerotic lesions. 6 Monocytes subsequently adhere to the endothelial cells, cross the endothelial layer to enter the subendothelial space, differentiate into macrophages, and eventually become foam cells. Macro- Nifedipine, an L-type...

Nifedipine prevents hepatic fibrosis in a non-alcoholic steatohepatitis model induced by an L-methionine-and choline-deficient diet

“…Ishii et al demonstrated that nifedipine activated PPARγ through the inactivation of ERK, leading to the suppression of MCP-1 and ABCA1 (ATP-binding cassette transporter, subfamily A, member 1) expression in macrophages. Nifedipine has also been reported to increase luciferase activity by full-length PPARγ but not by a PPARγ-GAL4 chimera, indicating that nifedipine is not a direct PPARγ ligand and may not increase intracellular natural PPARγ ligands, whereas nifedipine has an agonistic effect on PPARγ activity (13). Notably, amlodipine did not increase PPARγ activity, indicating that PPARγ activation is not a common effect of L-type calcium channel blockers.…”

“…Notably, amlodipine did not increase PPARγ activity, indicating that PPARγ activation is not a common effect of L-type calcium channel blockers. In addition, nifedipine was found to enhance the effects of other PPARγ agonists, pioglitazone and ciglitazone-induced PPARγ activation (13). Thus, the combination of nifedipine with thiazolidinediones may enhance the prevention of NAFLD or NASH in metabolic syndrome patients.…”

“…In contrast, nifedipine, an L-type calcium channel blocker, is known to have various favorable pleiotropic effects in several animal models, such as atherosclerosis, aortic aneurysmal formation and diabetic nephropathy models (12,13,19). Notably, one of the mechanisms of these effects would be mediation by PPARγ activation.…”

“…Thus, it is important to explore potential drug therapies to prevent the progression of NAFLD to NASH using the drugs already employed to treat such conditions. Among these numerous drugs, including antihypertensive, antidiabetic and antihyperlipidemic drugs, the present study focused on nifedipine, a calcium channel blocker that is widely used to treat hypertensive patients as several recent reports have demonstrated that nifedipine activates PPARγ activity in different cell types (12)(13)(14) (15). Briefly, the rats were divided into four groups: i) a group fed a control diet (sham, n=6); ii) a group fed an MCD diet (control: MCA, n=6); iii) a group fed an MCD diet and orally co-administered bizafibrate 10 mg/kg/day (bezafibrate: MCD + bezafibrate, n=7); and iv) a group fed an MCD diet and orally co-administered nifedipine 10 mg/kg/day (nifedipine: MCD + nifedipine, n=7).…”

l -Type Calcium Channel Inhibitor Diltiazem Prevents Aneurysm Formation by Blood Pressure–Independent Anti-Inflammatory Effects

“…Clinically, these are used to treat a variety of diseases including hypertension, angina pectoris, certain forms of cardiac arrhythmias, congestive heart failure, and hypertrophic cardiomyopathy. 10,11 Because aneurysm formation is a chronic inflammatory process, and several studies have linked LTCC blockers to anti-inflammatory effects in vitro 12 and in vivo, 13 we hypothesized that DIL attenuates aneurysm formation and tested this aspect in the ATII-infusion model of ApoE −/− mice.…”