“Sensing Danger” – A new player in the innate immune response during cardiac pressure overload

Pathological stress on the heart, as occurs during chronic pressure overload, either due to hypertension in humans or aortic constriction in animal models, induces a well known, but incompletely understood hypertrophic response. From the simplest of perspectives, cardiac hypertrophy is a suitable adaptation to increased afterload, and previous investigators have theorized that left ventricular hypertrophy (LVH) is a direct response to an increase in wall stress¹. Under physiologic conditions, such as pregnancy or exercise training, the growth of the heart is an adaptive response facilitating the ultimate goal of delivering adequate blood flow to the peripheral organs². In the case of pathological increases in afterload, the progression of concentric hypertrophy ultimately culminates in contractile dysfunction and overt failure³. Blocking or attenuating LVH in response to chronic pressure overload improves the cardiac function and attenuates the progression toward failure, even in the absence of reduced afterload^3,4.

Among several components of cardiac decompensation, mitochondrial dysfunction is a primary contributor to the pathogenesis of heart failure, and abnormal mitochondrial function, as a consequence of deficient mitophagy and mitochondrial quality control, can itself induce cardiomyopathy⁵. Indeed, disruption of ATP production by mitochondria in failing hearts due to multiple mechanisms, too numerous to address here, lead to adverse metabolic remodeling and has led to the general characterization as an energy deprived system⁶. However, disruption of the network of metabolic pathways linked to oxidative ATP synthesis by the mitochondria has greater implications beyond reduced energy supply for the heart, due to the consequential production of metabolic intermediates that serve as physiological effectors involved in intracellular signaling and deleterious chemical agents⁷. Thus, mitochondria play an active role, at multiple levels, in the pathogenesis of decompensatory cardiac hypertrophy in the development of heart failure.

One newly identified role for mitochondria in the development of heart failure is induction of a pro-inflammatory response mediated by a novel function of the mitochondrial antiviral-signaling protein (MAVS), as reported by Lin, et al, in this issue⁸. Inflammation is a well-reported and deleterious response to pathological stress, involving not only the heart, but also peripheral organs during the progression to heart failure^9,10. Mitochondria are already known to be a source of pro-inflammatory signaling leading to increased mitochondrial oxidative stress, and sterile inflammation is a significant factor in the pathogenesis of heart failure¹¹. Mitochondria contribute to sterile inflammation through release of reactive oxygen species and the release of damage associated molecular patterns (DAMP), such as mitochondrial DNA, cardiolipin, and N-formyl peptides. Like the pathogen-associated molecular patterns (PAMP), these DAMP can be sensed by Toll-like receptors and Nod-like receptors, which activate pro-inflammatory cytokines and inflammasomes, to stimulate innate immune cell activation and the resulting inflammation¹².

In their study, Lin, et al have identified the induction of an innate immune response to chronic pressure overload as a novel stimulus for the induction of LVH that implicates both impaired mitochondrial respiratory function and a pro-inflammatory response due to activation of MAVS⁸. Their work broadens our understanding of the mechanisms involved in the induction of LVH in response to cardiac stress. The investigators demonstrate induction of an innate immune response within the cardiomyocyte during chronic pressure overload, in the absence of any microbial infection, mediated through Nucleotide-binding oligomerization domain-containing protein 1 (Nod1) and its primary adapter protein, receptor-interacting protein 2 (RIP2). They have established for the first time a link between innate immune response activation through Nod1/RIP2 and the mitochondrial antiviral-signaling protein (MAVS), which is located on the outer mitochondrial membrane. MAVS had previously been identified as an important player in the innate immune response to viral infection¹³, and is so named for that. However, based on these newly reported findings, that nomenclature may belie its importance in responding to other stresses on the heart. In the present study, Lin, et al, were able to show that the innate immune response to pathological stress triggers a reduction in mitochondrial respiratory capacity and mitochondrial quality control mediated through MAVS. Reducing the expression of Nod1, RIP2 or MAVS not only attenuated the mitochondrial dysfunction but also reduced LVH. The findings implicate a broader role for previously known innate immune signaling agents in the cellular response to pathological stress, and unveil a new target mechanism for the inflammatory process in cardiac hypertrophy and heart failure.

The presence of a pathway that induces inflammation as a consequence of pathological stress on the heart is certainly not a new concept. However, identifying the linkage of an innate immune response to an inflammatory process mediated by a mitochondrial antiviral protein, which then regulates LVH is a newly identified mechanism and a potential target for mitigating the progression of decompensated cardiac hypertrophy toward heart failure. Indeed, chronic pressure overload appears to initiate a “danger signal” that invokes an innate immune response, not restricted to microbial infection that, at the very least, significantly contributes to both LVH and metabolic dysfunction, of which the terminal effector appears to be the mitochondrial response of MAVS.

Much remains to be explored with regards to Nod1/RIP2 signaling and their effect on mitochondrial function via MAVS activation in the intact heart. Chronic pressure overload leads to a number of metabolic alterations in terms of both substrate utilization patterns and metabolic rates⁷. Although the authors have presented some provocative results with regard to mitochondrial respiration in isolation, it remains to be seen how these observations from an organelle preparation translate to the intact beating heart and how these may interact with the immune response of an intact system, in vivo. The primary determinants of metabolic rate within the heart are substrate availability and workload. It will therefore be integral that the role of stress signaling through MAVS be evaluated in the intact beating heart to confirm the effects on cardiac metabolism and mitochondrial respiration, where physiological workload dominates ATP demand and production. Lin, et al actually found that reducing activation through MAVS led to a greater increase in glucose uptake following TAC compared to wild type hearts, potentially indicating that interruption of the innate immune response leads to an alternate metabolic response to TAC that remains abnormal. However, glucose uptake is nonspecific to any intracellular fate and does not distinguish among the possible fates of glucose to either be stored as glycogen or enter glycolysis, with or without ultimate entry into the oxidative metabolism of the mitochondria as pyruvate. Enhanced glucose uptake could similarly represent increased glycolysis due to impaired oxidative energy metabolism in the mitochondria, or equally so an increase in the ultimate oxidation of glucose. Whether, and to what possible extent, other metabolic pathways are altered in the absence of MAVS expression needs to be addressed. Thus, it remains to elucidate and understand how changes in MAVS content impact the metabolic plasticity of the heart in responding to other stresses.

In addition to the impacts on mitochondrial respiration and mitochondrial function, signaling through MAVS appears to have reciprocal effects on gene expression. There is an emerging understanding of how alterations in non-energy producing metabolic pathways within the failing heart participate in heart failure progression, that nonetheless involve and affect mitochondrial function⁷. Metabolic signaling from altered lipid dynamics influences transcriptional regulation of metabolic gene expression and lipotoxic damage due to remodeled lipid profiles¹⁴, while altered glucose metabolism affects post translational modifications of key regulatory proteins in the pathologically stressed heart¹⁵. And in the present study, NOD1/RIP2 signaling affected mitochondrial function via MAVS activation with reciprocal effects on gene expression.

The propagation of the initial “danger signal” to the mitochondria through MAVS, although it would appear maladaptive, is another example of how the pathological state of the heart is communicated to the mitochondria⁷ via activation of the MAVS protein at the outer membrane. The novel findings by Lin, et al, contribute yet another wrinkle in our understanding of the central role mitochondria play in both sensing and adapting to cardiac stress. In particular, the newly elucidated role of MAVS adds to the list of pro-inflammatory responses in the pathogenesis of heart failure, one that contributes to a feedback loop with mitochondrial oxidative metabolism and respiratory function ⁷. Unfortunately, many of the mitochondrial responses to pathological stress on the heart eventually do become maladaptive, and for that reason the mitochondria and associated signaling pathways remain important therapeutic targets in the treatment of cardiac stress and LVH. Finally, a word of caution is appropriate. Although the present study reveals that the induction of an innate immune response participates in the progression of LVH and heart failure, any consideration of the innate immune response as a therapeutic target must recognize the cardioprotective action of MAVS expression in models of viral myocarditis¹³.