Anaemia is associated with severe RBC dysfunction and a reduced circulating NO pool: vascular and cardiac eNOS are crucial for the adaptation to anaemia

Abstract

Anaemia is frequently present in patients with acute myocardial infarction (AMI) and contributes to an adverse prognosis. We hypothesised that, besides reduced oxygen carrying capacity, anaemia is associated with (1) red blood cell (RBC) dysfunction and a reduced circulating nitric oxide (NO) pool, (2) compensatory enhancement of vascular and cardiac endothelial nitric oxide synthase (eNOS) activity, and (3) contribution of both, RBC dysfunction and reduced circulatory NO pool to left ventricular (LV) dysfunction and fatal outcome in AMI. In mouse models of subacute and chronic anaemia from repeated mild blood loss the circulating NO pool, RBC, cardiac and vascular function were analysed at baseline and in reperfused AMI. In anaemia, RBC function resulted in profound changes in membrane properties, enhanced turnover, haemolysis, dysregulation of intra-erythrocytotic redox state, and RBC-eNOS. RBC from anaemic mice and from anaemic patients with acute coronary syndrome impaired the recovery of contractile function of isolated mouse hearts following ischaemia/reperfusion. In anaemia, the circulating NO pool was reduced. The cardiac and vascular adaptation to anaemia was characterised by increased arterial eNOS expression and activity and an eNOS-dependent increase of end-diastolic left ventricular volume. Endothelial dysfunction induced through genetic or pharmacologic reduction of eNOS-activity abrogated the anaemia-induced cardio-circulatory compensation. Superimposed AMI was associated with decreased survival. In summary, moderate blood loss anaemia is associated with severe RBC dysfunction and reduced circulating NO pool. Vascular and cardiac eNOS are crucial for the cardio-circulatory adaptation to anaemia. RBC dysfunction together with eNOS dysfunction may contribute to adverse outcomes in AMI.

Interplay of the red blood cell and vascular endothelial nitric oxide synthase system to combat cardiac complications of anemia

“…With the present studies, Wischmann et al show that cardiovascular protection against I/R damage in response to acute myocardial infarction (AMI) is mainly based on endogenous • NO formation from either red blood cell (RBC, e.g., by nitrite bioactivation or RBC-eNOS) or vascular/cardiac eNOS [28]. In a mouse model of anemia, the authors demonstrate that AMI-induced mortality is more pronounced due to impaired RBC-derived • NO formation as also seen with the increase in AMI mortality upon pharmacological eNOS inhibition by l-NAME.…”

“…Thus, in summary, the results of this highly important study demonstrate that moderate blood loss anemia is associated with severe red blood cell dysfunction and increased superoxide production, which may be related at least in part to eNOS uncoupling in RBC leading to a reduction of the • NO pool. In addition, Wischmann et al also established with a series of well-designed experiments for the first time that vascular and cardiac eNOS are crucial for the cardiocirculatory adaptation to anemia in particular in the setting of I/R [28]. The presented findings will help to improve therapeutic strategies in the setting of AMI and anemia.…”

“…The protective effects are lost by genetic or pharmacological eNOS inhibition. Implications for the novel findings on interplay of red blood cell/vascular eNOS for cardioprotection in a model of anemia are described [28]. In principle, anemic patients have a worse prognosis after AMI or ACS due to dysfunctional RBC • NO signaling, but upregulation of eNOS activity in the heart and vessels of anemic patients provides compensatory protection that is lost upon genetic or pharmacological eNOS inhibition.…”

“…All these different regulators of eNOS activity, • NO formation and endothelial function are summarized in the Fig. 1 and have been-reviewed previously [18,22], and put into context with the novel findings by Wischmann et al [28].…”

“…The mechanism of cardioprotection described in the clinically important study by Wischmann et al is based on the assumption of a compensatory enhancement of vascular endothelial nitric oxide synthase (eNOS) activity and nitric oxide ( • NO) formation in anemic mice, when red blood cell (RBC) eNOS function and • NO formation are impaired [28]. The cardioprotective properties of eNOS and • NO are widely accepted and were extensively reviewed in the past [9,24] and redefined in recent years [3].…”