Lipoprotein(a)/CD36 Interaction Drives IL-6/RhoA-GTP Signaling and miRNA Epigenetic Regulation in Coronary Artery
Yen-Kuang Lin1,2, Tsung-Han Hsieh3, Chi-Tai Yeh4,5
1Graduate Institute of Athletics and Coaching Science, National Taiwan Sport University, No. 250 Wenhua 1st Rd., Guishan, Taoyuan 33301, Taiwan.
Insights
Elevated Lipoprotein(a) [Lp(a)] drives coronary artery spasm (CAS) by activating the CD36/interleukin-6/RAS Homolog Family Member A (RhoA)-GTP pathway. This study reveals Lp(a)/CD36 signaling as a key mechanism in CAS development.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Lipoprotein(a) [Lp(a)] contributes to coronary artery spasm (CAS) through vascular smooth muscle cell contraction.
- The specific role of the soluble CD36 (sCD36)/interleukin (IL)-6/RAS Homolog Family Member A (RhoA)-GTP pathway in Lp(a)-mediated CAS remains unclear.
Purpose of the Study:
- To investigate the interaction between Lp(a) and the sCD36/IL-6/RhoA-GTP signaling pathway in CAS.
- To elucidate the molecular mechanisms underlying Lp(a)-induced inflammation and HCASMC activation in CAS development.
Main Methods:
- Expression profile correlation analyses, molecular docking, RNA sequencing, flow cytometry, immunoblotting, and quantitative reverse transcription polymerase chain reaction were employed.
- Investigated Lp(a)/CD36 signaling in CAS patient monocyte-derived macrophages (PMDMs) and human coronary artery smooth muscle cells (HCASMCs).
Main Results:
- CAS patients exhibited significantly higher plasma Lp(a) and sCD36 levels, which were positively correlated.
- Lp(a) treatment induced co-overexpression of CD36 and RhoA in PMDMs and HCASMCs, enhancing their mRNA and protein expression dose-dependently.
- CD36 knockdown or amentoflavone treatment suppressed Lp(a)-induced expression of CD36, RhoA-GTP, IL-6, TNF-α, NF-κB, and CD80 in HCASMCs.
Conclusions:
- Elevated Lp(a) upregulates the CD36-dependent TNF-α/NF-κB/IL-6/RhoA-GTP signaling pathway in CAS PMDMs and HCASMCs.
- Lp(a)/CD36 inflammatory signaling, HCASMC activation, and macrophage M1 polarization are key mediators in the development of CAS.
Abstract:
Background: Lipoprotein(a) [Lp(a)]-induced inflammation contributes to coronary artery spasm (CAS) by the contraction of vascular smooth muscle cells. However, the interaction between Lp(a) and soluble CD36 (sCD36)/interleukin (IL)-6/RAS Homolog Family Member A (RhoA)-GTP signaling pathway has not been evaluated. Methods: We investigated the relevance of Lp(a)/CD36 signaling in CAS patient monocyte-derived macrophages (PMDMs) and a human coronary artery smooth muscle cell (HCASMC) line using expression profile correlation analyses, molecular docking, RNA sequencing, flow cytometry, immunoblotting, and quantitative reverse transcription polymerase chain reaction. Results: Plasma Lp(a) and sCD36 levels in 41 CAS patients were significantly higher (p = 0.001) and positively correlated (r2 = 0.3145, p < 0.001), a trend not observed in 36 non-CAS controls. RNA sequencing indicated a significant co-overexpression of CD36 and RhoA in Lp(a)-treated CAS PMDMs and HCASMCs, of which the mRNA and protein expression of CD36 and RhoA were significantly enhanced (p < 0.001) dose-dependently. Lp(a) rather than LDL preferentially induced CD80+ PMDM (M1) polarization. In HCASMCs, the CD36 knockdown using either short hairpin RNA or natural biflavonoid amentoflavone suppressed Lp(a)-upregulated protein expression of CD36, RhoA-GTP, IL-6, tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB, and CD80; however, overexpressed CD36 increased their levels. Lp(a) decreased and amentoflavone increased the epigenetic expression of CD36 inhibitors, miR-335-5p, and miR-448, respectively. Reciprocally, an miRNA inhibitor or mimic could magnify or diminish Lp(a)-induced CD36, TNF-α, NF-κB and IL-6 expressions in HCASMCs, respectively. Conclusions: Elevated Lp(a) levels upregulate the CD36-dependent TNF-α/NF-κB/IL-6/RhoA-GTP signaling pathway in CAS PMDMs and HCASMCs, indicating that Lp(a)/CD36 inflammatory signaling, HCASMC activation, and macrophage M1 polarization mediate CAS development.
