Critical Role for Leukocyte Hypoxia Inducible Factor-1α Expression in Post-Myocardial Infarction Left Ventricular Remodeling

Abstract

Rationale : Hypoxia inducible factor (HIF)-1α is a transcription factor stabilized by hypoxia. It regulates cytokines involved in the inflammatory response after ischemia and affects white blood cell (WBCs) function. The effect of HIF-1α on WBC function and inflammation following myocardial infarction (MI) is unknown. Objective : We assessed peritoneal and myocardial inflammation in the setting of low WBC HIF-1α expression through bone marrow transplantation of hematopoietic stem cells transfected with scramble or HIF-1α small interfering (si)RNA. Methods and Results : Rosa hematopoietic stem cells (lin − , cKit + ) were transfected with a green fluorescent protein (GFP) reporter lentivirus encoding a siRNA to HIF-1α or scramble. Irradiated 6- to 8-week-old C57/BL6J mice received 50 000 GFP + HIF-1α or scramble siRNA-transfected hematopoietic stem cells. Peritonitis or myocardial infarction via left anterior descending coronary artery ligation was induced 6 weeks after bone marrow transplantation. In the peritonitis model, HIF-1α siRNA group exhibited a significant decrease in neutrophil and monocyte entry to the peritoneum compared to scramble mice. Similarly neutrophil infiltration into the infarct zone was decreased in the HIF-1α siRNA group. No difference of myocardial infarct size was observed between groups. Interestingly, the ejection fraction were similar in both groups at baseline and 3 days post-MI but increased significantly in the HIF-1α siRNA group compared to control beginning 7 days after MI. Gene array studies demonstrated that downregulation of WBC HIF-1α was associated with decreased WBC CCR1, -2, and -4 expression. Chemotaxis assay results confirmed that decreased monocyte migration induced by downregulation of HIF-1α was partially reversed by overexpression of CCR2. Conclusions : Downregulation of leukocyte HIF-1α expression resulted in decreased recruitment of WBC to the sites of inflammation and improvement in cardiac function following MI. Downregulation of HIF-1α suppressed WBC cytokine receptors CCR1, -2, and -4, which are necessary for WBC mobilization and recruitment to inflammatory cytokines following MI. The effects of downregulation of leukocyte HIF-1α on WBC migration are attributable, at least in part, to the decreased CCR2 expression. These results demonstrate that WBC infiltration into the newly injured myocardium plays a significant role in left ventricular remodeling, but not infarct size.