Mitochondrial reactive oxygen species determine murine macrophage responses to pressure-overload in a sex-dependent manner

Background and purpose:

The extent of pressure-overload induced left ventricular (LV) remodelling and dysfunction is exacerbated by myocyte mitochondrial emission of reactive oxygen species (ROS) deriving from the switch of the nicotinamide nucleotide transhydrogenase (NNT) to reverse mode in male C57Bl6 N mice. Concomitantly, LV afterload evokes an early and transient LV expansion of immune cells and herein especially of macrophages exerting adaptive or maladaptive effects depending on their origin and polarisation. We aimed at investigating whether NNT-dependent mitochondrial ROS emission represents a crucial upstream event driving maladaptive macrophage responses of the pressure-overloaded heart - and if so, whether targeting ROS by mitochondrial catalase (mCAT) could rescue the phenotype.

Methods and results:

14 wks old male and female mice heterozygous for NNT (wt/t) or with truncated NNT (t/t) in the presence or absence of overexpressed mCAT were randomly assigned to transverse aortic constriction (TAC) or sham surgery for 1 week. In males, but not females, heterozygous NNT promoted TAC-triggered cardiac accumulation of resident macrophages while overall macrophage expansion and recruitment was fully blunted in the presence of mCAT. In line with prevention of macrophage recruitment, mCAT overexpression attenuated TAC-induced up-regulation of femoral Csf-1, Ccr2, Adrb2, Vcam-1 and Icam-1 in wt/t males, factors known to be involved in haematopoiesis, stem cell release, myelopoiesis and immune cell migration in response to pressure-overload. Of note, in t/t males, the afterload-induced inflammation was less pronounced and remained fully unaffected by mCAT. These observations underpin the hypothesis that LV remodelling exacerbated by the NNT reverse mode involves a direct ROS-macrophage communication. Yet, interestingly, in contrast to the male cohort, in females, NNT expression did not promote but fully prevented LV accumulation of macrophages and herein especially of reparative subsets. Lack of reparative macrophage expansion is suggested to drive maladaption to pressure-overload, as confirmed by concurrently potentiated Nppb expression in wt/t females. These NNT effects remained fully unaffected by concurrent mCAT expression.

Conclusion:

Our data suggest NNT to exert divergent action modes in females and males and mitochondrial ROS to be crucially involved in macrophage responses to LV pressure-overload. Targeted interference with NNT activity could represent a novel sex-specific therapeutic strategy to prime macrophages toward reparative responses.