Title : PCSK9 affect ventricular remodeling after myocardial infarction through regulation of regulatory T cells
Abstract:
Objective: To explore the effects and potential mechanisms of PCSK9 on ventricular remodeling after myocardial infarction.
Methods: Mouse were used to construct a model of acute myocardial infarction.To assess the effect of PCSK9, we used WT mice treated with PCSK9 inhibitor (alirocumab) or PCSK9-/-mice. Regulatory T (Treg) cells in WT mice were depleted by intraperitoneal injection of CD25 antibody. Cardiac function was assessed by cardiac ultrasound on day 1, 14 and 28 after successful construction of the myocardial infarction model; the infarct size was measured by Masson staining of tissue sections, the cross-sectional area of cardiomyocytes was measured by WGA staining and the collagen content was assessed by Sirius Red (PSR) staining 28 days after myocardial infarction. The proportion of Treg cells, proliferative Treg cells, M1 and M2 macrophages in the cardiac tissue was analyzed by flow cytometry on day 7 after myocardial infarction. The induced human iTreg cells were treated with human-derived PCSK9 recombinant protein-treated, and the cellular reactive oxygen species (ROS) level and cell proliferation was analyzed by flow cytometry.
Results: Knockdown and inhibition of PCSK9 improved cardiac function, reduced infarct size and cross-sectional area of cardiomyocytes, increased collagen content in the margins of the infarct zone, and increased the proportion of Treg cells and proliferative Treg cells in cardiac tissue. PCSK9 inhibitor promoted M2 polarization of macrophages in cardiac tissue. PCSK9 recombinant protein promoted ROS production and inhibited proliferation of human iTreg cells. After depletion of Treg cells in mice, PCSK9 inhibitor did not improve cardiac function.
Conclusion: Knockdown and inhibition of PCSK9 alleviated ventricular remodeling after myocardial infarction by regulating the proportion of Treg cells in cardiac tissue and promoting proliferation.
Audience Take Away
- This study uncovered the effects of PCSK9 on Treg cells, broadening its pleiotropy
- We found that PCSK9 plays an important role in immune regulation after myocardial infarction, and more in-depth mechanisms can continue to be explored
- This study may broaden the clinical indications for PCSK9 inhibitors, and clinical studies can be conducted to confirm
