Telmisartan Enhances Cholesterol Efflux from THP-1 Macrophages by Activating PPARγ

Abstract

Aim:The ATP binding cassette transporters A1 and G1 (ABCA1/G1) and scavenger receptor class B type (SR-B ) are key molecules in cholesterol efflux and atherogenesis. These genes are regulated by peroxisome proliferator-activated receptor (PPAR ) and liver X receptor (LXR). Telmisartan is an angiotensin type 1 receptor blocker which has been reported to act as a ligand for PPAR . We investigated whether PPAR -activating ARBs affect the expression of these genes and cholesterol efflux from macrophages. Methods and Results: Telmisartan increased ABCA1, ABCG1 and SR-B mRNA levels in THP-1 macrophages in a dose-and time-dependent fashion. It also increased their protein levels and enhanced apoA--and HDL-mediated cholesterol efflux from macrophages. The knockdown of PPAR by siRNA abolished the telmisartan-induced expression of these genes. The knockdown of LXR resulted in the complete and partial abolishment of telmisartan-induced ABCA1 and ABCG1 expression, respectively. We also demonstrated that telmisartan-induced SR-B expression was dependent on the PPAR pathway but not on the LXR pathway. A luciferase assay using an ABCA1 promoter construct showed that telmisartan activated ABCA1 transcription, which was abolished if the LXR binding element was mutated, indicating that increased ABCA1 transcription by telmisartan is LXRdependent. Conclusion: Our results showed that telmisartan enhanced both apoA--and HDL-mediated cholesterol efflux from macrophages by increasing ABCA1, ABCG1 and SR-B expression via PPAR -dependent and LXR-dependent/independent pathways.

Genotypic Effect of ABCG1 Gene Promoter -257T>G Polymorphism on Coronary Artery Disease Severity in Japanese Men

“…LXRs form obligate heterodimers with RXR. The LXR/RXR heterodimer binds to lipogenic target gene promoters such as 7 -hydroxylase (CYP7A), apoE, cholesterol ester transfer protein, SREBP1c, ABCA1, and ABCG1, all of which contain a direct repeat 4 element in their promoter, i.e., two direct hexameric repeats separated by four nucleotides 27,29) . The ABCG1 gene has at least two promoters, one upstream of exon 1 and the other upstream of exon 5, and encodes for several transcripts 19,20) .…”

Beneficial Effects of Exercise-Based Cardiac Rehabilitation on High-Density Lipoprotein-Mediated Cholesterol Efflux Capacity in Patients with Acute Coronary Syndrome

“…It was shown that PPAR agonist increased ATP-binding cassette A1 (ABC A1) in liver X receptor (LXR)-dependent manner, which resulted in enhanced cholesterol efflux capacity 18) . In addition, our group reported that addition of telmisartan, a PPAR -activating angiotensin type 1 receptor blocker to cell cultures also increased ABC A1 and LXR in macrophage gene expression and enhanced cholesterol efflux capacity from THP-1 macrophages 19). However, little is known about the effects of CR with cardiovascular medication on HDL cholesterol efflux capacity 12,20) .…”

“…Cholesterol efflux capacity was performed by experienced analysts at National Defense Medical College who were blinded to the clinical characteristics of the patients according to the methods used by Khera et al 12,14,[16][17][18][19][20] . J774 macrophages were purchased from RIKEN (Tsukuba, Japan), cultured in RPMI1640 medium containing 10% fetal bovine serum, and kept under constant conditions of 5% carbon dioxide and a temperature of 37 .…”

Serum high-molecular-weight adiponectin as a marker for the evaluation and care of subjects with metabolic syndrome and related disorders

“…We recently reported that changing the treatment to losartan/HCTZ from a usual dosage of ARB, provided good blood pressure control, while the HMW-adiponectin level remained unchanged in male subjects with hypertension 46) . We have found that administering telmisartan, which also has partial PPAR activity in vitro [47][48][49][50] , increased the serum HMW adiponectin concentration in Japanese males with hypertension and abdominal obesity 51) .…”