Cav3.1 T-type calcium channel blocker NNC 55-0396 reduces atherosclerosis by increasing cholesterol efflux

Abstract

Calcium channel blockers (CCBs) are commonly used as antihypertensive agents. While certain L-type CCBs exhibit antiatherogenic effects, the impact of Cav3.1 T-type CCBs on antiatherogenesis and lipid metabolism remains unexplored. NNC 55–0396 (NNC) is a highly selective blocker of T-type calcium channels (Cav3.1 channels). We investigated the effects of NNC on relevant molecules and molecular mechanisms in human THP-1 macrophages. Cholesterol efflux, an indicator of reverse cholesterol transport (RCT) efficiency, was assessed using [3H]-labeled cholesterol. In vivo, high cholesterol diet (HCD)-fed LDL receptor knockout (Ldlr-/-) mice, an atherosclerosis-prone model, underwent histochemical staining to analyze plaque burden. Treatment of THP-1 macrophages with NNC facilitated cholesterol efflux and reduced intracellular cholesterol accumulation. Pharmacological and genetic interventions demonstrated that NNC treatment or Cav3.1 knockdown significantly enhanced the protein expression of scavenger receptor B1 (SR-B1), ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), and liver X receptor alpha (LXRα) transcription factor. Mechanistic analysis revealed that NNC activates p38 and c-Jun N-terminal kinase (JNK) phosphorylation, leading to increased expression of ABCA1, ABCG1, and LXRα-without involving the microRNA pathway. LXRα isrequired for NNC–induced ABCA1 and ABCG1 expression. Administering NNC diminished atherosclerotic lesion area and lipid deposition in HCD-fed Ldlr-/- mice. NNC's anti-atherosclerotic effects, achieved through enhanced cholesterol efflux and inhibition of lipid accumulation, suggest a promising therapeutic approach for hypertensive patients with atherosclerosis. This research highlights the potential of Cav3.1 T-type CCBs in addressing cardiovascular complications associated with hypertension.