Role of Endothelial Cells in Myocardial Ischemia-Reperfusion Injury

Abstract

Minimizing myocardial ischemia-reperfusion injury has broad clinical implications and is a critical mediator of cardiac surgical outcomes. "Ischemic injury" results from a restriction in blood supply leading to a mismatch between oxygen supply and demand of a sufficient intensity and/or duration that leads to cell necrosis, whereas ischemia-reperfusion injury occurs when blood supply is restored after a period of ischemia and is usually associated with apoptosis (i.e. programmed cell death). Compared to vascular endothelial cells, cardiac myocytes are more sensitive to ischemic injury and have received the most attention in preventing myocardial ischemia-reperfusion injury. Many comprehensive reviews exist on various aspects of myocardial ischemia-reperfusion injury. The purpose of this review is to examine the role of vascular endothelial cells in myocardial ischemia-reperfusion injury, and to stimulate further research in this exciting and clinically relevant area. Two specific areas that are addressed include: 1) data suggesting that coronary endothelial cells are critical mediators of myocardial dysfunction after ischemia-reperfusion injury; and 2) the involvement of the mitochondrial permeability transition pore in endothelial cell death as a result of an ischemia-reperfusion insult. Elucidating the cellular signaling pathway(s) that leads to endothelial cell injury and/or death in response to ischemia-reperfusion is a key component to developing clinically applicable strategies that might minimize myocardial ischemia-reperfusion injury.

Keywords: Myocardial ischemia-reperfusion injury; endothelial cells; mitochondrial permeability transition pore.

Fig. (1)

Panel A. Pretreatment with the sodium-hydrogen exchanger isoform 1 (NHE1) using cariporide attenuates regional dysfunction in response to 25 cycles of ischemia (I, 2-min) and reperfusion (R, 8-min) of the left circumflex coronary artery (LCx) in conscious swine. Reversible occlusions of the left circumflex coronary artery were performed using a hydraulic occluder. Systolic wall thickening (sonomicrometry) was assessed in the normally perfused (left anterior descending, LAD) and risk (left circumflex coronary artery, LCx) regions. Six animals completed three protocols each separated by one week: 1) I/R + VEHICLE (25 I/R cycles + saline infusion); 2) I/R + CARIPORIDE (25 I/R cycles + Cariporide); and 3) SHAM (vehicle administration for 4.2 hours i.e. the occluder was never inflated). Systemic hemodynamics were similar among and within each protocol (data not shown). Blood flow measured during LCx occlusion (microspheres) confirmed that perfusion was reduced (p < 0.05) in the LCx vs. LAD regions. During I/R + VEHICLE, LCx systolic wall thickening was reduced (*p < 0.05) after five IR cycles, and a stable reduction (approximately 55% of baseline; p < 0.05) was present after 20 I/R cycles. During I/R + CARIPORIDE, LCx systolic wall thickening was reduced (*p < 0.05) only after 15 and 25 I/R cycles (approximately 80 and 72%, respectively). The decrease in systolic wall thickening was greater in I/R + VEHICLE vs. I/R + CARIPORIDE (#p < 0.05). LCx systolic wall thickening was not altered during SHAM, while LAD systolic wall thickening was similar within and among all protocols. These findings indicate NHE1 inhibition delays the onset and limits the degree of regional dysfunction in response to repeated bouts of ischemia and reperfusion. Panel B. Pretreatment with cariporide limits I/R –induced coronary microvascular stunning. Anesthetized rats (~ 10 per group) completed 2 × 10-min coronary artery occlusions separated by 5-min of reperfusion, followed by 15 or 60 min of reperfusion (I/R). Cariporide or vehicle was administered 15 min before ischemia (or sham-operation) and was continued throughout each protocol. After reperfusion, hearts were excised, and the reactivity of resistance arteries (internal diameter, ~115 μm) was assessed. The maximal response to acetylcholine-induced relaxation was blunted (*p< 0.05) in I/R + VEHICLE (~35%) and I/R + CARIPORIDE (~55%), compared with sham-operated animals (~85%). However, the percent relaxation to acetylcholine was greater (#p<0.05) in vessels from I/R + CARIPORIDE and SHAM-operated rats vs. I/R + VEHICLE animals. Relaxation to sodium nitroprusside was not different among groups (data not shown). Results were similar in vessels obtained from animals after 60 min or 15-min of reperfusion. These findings indicate NHE1 inhibition before coronary occlusion lessens ischemia-induced microvascular dysfunction for 15–60 min after reperfusion. This figure is reprinted with permission from the American Physiological Society (APS) from “Na+/H+ exchange subtype 1 inhibition reduces endothelial dysfunction in vessels from stunned myocardium” Am J Physiol Heart Circ Physiol 2001 281: H1575H1582, APS identifier H925-0].

Fig. (2)

Correlation between cardiac function and coronary flow. Isolated hearts were perfused at 80 mmHg for 30-min with Krebs-Henseleit buffer at 37 °C. Next, hearts completed 30-min of no-flow ischemia followed by 60-min reperfusion. Cardiac functional measurements were obtained immediately at the end of reperfusion. Left ventricular (LV) developed pressure (LVDP, mmHg), and positive and negative (−) LV dP/dt (mm Hg/sec) correlated significantly with coronary flow [98].

Fig. (3)

The reperfusion injury signaling kinase (RISK) pathway. Pharmacological agents, ischemic preconditioning and/or ischemic postconditioning can activate PI3K to precipitate Akt phosphorylation. Akt phosphorylation might prevent opening of the mitochondrial permeability transition pore (MPTP) via endothelial nitric oxide synthase (eNOS). This would be protective because MPTP opening is believed to be an irreversible step toward cell death. CSA, cyclosporine; SFA, sanglifehrin A.

Fig. (4)

The mitochondrial permeability transition pore (MPTP) consists of three proteins: adenine nucleotide translocator (ANT); voltage dependent anion conductance (VDAC); and cyclophilin D (CyD). When cyclosporine (CSA) binds to CyD pore opening is prevented and IR injury is limited. Atractyloside is an MPTP opener that exacerbates IR injury.