Abstract 10610: Cxcr4 Overexpression Promotes Mitochondrial Function to Protect Against Ischemia-reperfusion-induced Cardiomyocyte Death
Background and Objective: The chemokine (C-X-C motif) receptor 4 (CXCR4) is expressed on native cardiomyocytes and can decrease isolated cardiomyocyte contractility. Here, we examine the role of CXCR4 in cardiomyocyte response to ischemia-reperfusion (I/R) injury.
Methods and Results: Isolated adult rat ventricular cardiomyocytes were subjected to hypoxia/re-oxygenation (H/R) to simulate ischemia/reperfusion (I/R) injury. The decrease in CXCR4 expression by 35%, 55% and 77% at 4, 7 and 9 hours after re-oxygenation was associated with dysfunctional energy metabolism indicated by an increased ADP/ATP ratio. To examine a possible nexus, we investigated whether CXCR4 over-expression (OE) can prevent bio-energetic disruption-associated cell death using adenoviral infection of cardiomyocytes with CXCR4 encoding-gene or non-translated nucleotide sequence (Control). Indeed, there was 2.5-fold increase in CXCR4 expression level in cardiomyocytes post CXCR4-adenovirus transduction. Although the same extent of H/R-provoked cytosolic calcium overload (~1.3-fold) was measured (Fig. 1A), the hydrogen-peroxide-induced the decay of mitochondrial membrane potential (Δψm) was suppressed in CXCR4 OE group compared with Control group (Fig. 1B). Despite calcium overload, mitochondrial swelling was significantly attenuated in CXCR4 group, implicating that CXCR4 OE prevents permeability transition pore (mPTP) opening (Fig. 1C). Consequently, in the presence of H/R, mitochondrial dysfunction was mitigated (Fig. 1D) and cardiomyocyte death was decreased to 65% in the CXCR4 OE group, compared with the control group.
Conclusion: While ATP production and CXCR4 expression in cardiomyocytes are decreased by ischemia-reperfusion injury, CXCR4 OE can alleviate mitochondrial swelling and prevent energy disruption to improve cardiomyocyte survival.
- © 2013 by American Heart Association, Inc.