Emerging pathways of communication between the heart and non-cardiac organs

Abstract

The breakthrough discovery of cardiac natriuretic peptides provided the first direct demonstration of the connection between the heart and the kidneys for the maintenance of sodium and volume homeostasis in health and disease. Yet, little is still known about how the heart and other organs cross-talk. Here, we review three physiological mechanisms of communication linking the heart to other organs through: i) cardiac natriuretic peptides, ii) the microRNA-208a/mediator complex subunit-13 axis and iii) the matrix metalloproteinase-2 (MMP-2)/C-C motif chemokine ligand-7/cardiac secreted phospholipase A2 (sPLA2) axis – a pathway which likely applies to the many cytokines, which are cleaved and regulated by MMP-2. We also suggest experimental strategies to answer still open questions on the latter pathway. In short, we review evidence showing how the cardiac secretome influences the metabolic and inflammatory status of non-cardiac organs as well as the heart.

Keywords

heart / liver / metabolism / inflammation / natriuretic peptides / microRNA / matrix metalloproteinase

Introduction

Diseases with strong metabolic and inflammatory components (ischemic heart disease, arthritis, neurodegeneration and cancer) are leading causes of morbidity, extremely high costs associated with health care, and mortality worldwide^[1]. Given the incomplete understanding of these diseases, new studies to decipher organ-specific cross-talk between inflammation and metabolic pathways are constantly needed.

This paper aims to: (i) introduce historical background for the groundbreaking notion that the heart exerts an endocrine function^[2–^5], (ii) review briefly two other recent mechanisms- the cardiac-specific microRNA (miR)-208a/mediator complex subunit-13 (MED13) axis^[6] and the matrix metalloproteinase 2 (MMP-2)/C-C motif chemokine ligand 7 (CCL7)/cardiac secretory phospholipase A2 (sPLA2) axis- by which the heart modulates lipid metabolism in non-cardiac organs (e.g., the liver)^[7–^9] and (iii) suggest experimental approaches to elucidate the mechanism that regulates the cardiac-specific origin of sPLA2 in MMP-2 deficiency as well as delineate the biochemical pathway by which the dyad of MMP-2 and monocyte-chemotactic protein 3 (MCP-3)/CCL7 modulates cholesterol homeostasis in the heart and other organs. Outputs of this latter line of research have the potential to open up new avenues for modulating cholesterol metabolism [e.g., at the levels of MMP-2 activity or signaling mediators positioned downstream of C-C chemokine receptor type 2 (CCR2)] in inflammatory and metabolic disorders.

The heart has an endocrine function consisting of the release of natriuretic peptides

Rows 1 to 8 in Table 1 show selected discoveries related to the ability of the heart atrial muscle cells of mammals to synthesize, store within specific atrial granules, and release cardiac natriuretic peptides (cNPs). The mechanism of action of cNPs is summarized in Box 1. These findings by the research team of Dr. de Bold were the first direct demonstration that the heart has an endocrine function (summarized in Table 1, rows 1 to 8). In Table 2, we summarize selected observations describing how the cNP system influences hypertrophic growth, fibrosis, and cardiac remodeling/dysfunction. For a summary of the influences of cNPs on adipose tissue biology and metabolism, please see Table 3.

A cardiac-specific miR-208a/MED13 axis further connects the heart with other organs

Recent studies^[6,⁵⁰–^51] have identified cardiac-specific miR-208a as a negative regulator of the subunit 13 of mediator complex MED13 (summarized in Table 1, row 10). MED13 regulates the transcription of many nuclear receptor genes involved in fatty acid oxidation as well as influencing the activity of as-yet-unidentified secreted/circulating factors, which connect the activity of cardiac MED13 with the metabolism and energy homeostasis program of non-cardiac organs, such as the liver and adipose tissue (row 10 of Table 1).

MMP-2 deficiency is associated with elevated secreted/circulating cardiac PLA2 activity

In 2015, a possibly new endocrine system was postulated, by which the heart influences cardio-hepatic lipid metabolism, hepatic sensitivity to dietary cholesterol, systemic inflammatory status, severity of fever and energy expenditure^[7–^9]. By investigating the pathophysiological consequences of MMP-2 deficiency in MMP-2 null (Mmp2^-/-) mice, it was found that MMP-2 governs the secretion of a highly pro-inflammatory cardiac-specific phospholipase A2 activity (named ‘cardiac’ sPLA2). This finding provides a plausible and novel mechanism that could explain, at least partially, why human MMP-2 deficiency results in pediatric inflammatory arthritis with relentless bone loss, inflammation, cardiac developmental defects and other metabolic abnormalities such as hirsutism and dwarfism^[7–^9]. Two years after the identification of the MMP-2/cardiac sPLA2 axis^[7–^9], there are key questions which warrant further investigation including: What is the molecular identity of the MMP-2-regulated sPLA2? What determines the cardiac origin of this sPLA2 in MMP-2 deficiency? We address these questions in the sections below.

Cardiac sPLA2 may belong to the family of classical secreted phospholipases but its molecular composition is unknown

Up to now unsuccessful, previous attempts to identify cardiac sPLA2 have used targeted time-resolved immunofluorescence assays (TRIFA)^[8] or RT-PCR with reagents targeting the 31 different PLA2s (including classical and atypical, cytosolic and secreted enzymes)^[7–^8] as well as conventional mass spectrometry, which is not inherently quantitative (the authors’ unpublished data). Activity inhibition studies have suggested that cardiac sPLA2 may be a mixture of indoxam-resistant (e.g., PLA2G1B, PLA2G2D, PLA2G2F, PLA2G10) and indoxam-sensitive (e.g., PLA2G2E, PLA2G5) sPLA2s or a new member of the sPLA2 family^[8].

To date, identifying the isoforms responsible for cardiac sPLA2 activity has been challenging calling for unbiased, highly sensitive and quantitative identification strategies such as a proteomics approach coupled with stable isotope-labelling with amino acids in vivo (mouse SILAC), a technique that has revolutionized the field of quantitative proteomics making it feasible to quantitate protein expression in mouse organs in two states^[52–^53]. Applying such a strategy (Box 2) has the added advantages of enabling the identification and quantification of all PLA2s deregulated (up- or down-regulated) in MMP-2-deficiency along with any other proteomics abnormalities. These resultant proteomic signature of MMP-2 deficiency could serve as biomarker of disease activity or as new therapeutic target in patients.

MMP-2, CCL7 and organ-homing immune cells govern cardiac sPLA2 release in an organ-specific fashion

Recent studies indicate that CCL7 (a small pro-inflammatory cytokine which is normally cleaved and inactivated by MMP-2) serves as stimulus for cardiac-specific release of sPLA2 activity^[8]. This notion is supported by (a) ex vivo assays data^[7], showing that CCL7 stimulates sPLA2 release from cardiac, but not hepatic tissue and (b) the normalization of the cardio-hepatic lipid metabolic phenotype of MMP-2-deficient mice injected with neutralizing CCL7 antibodies, but not with isotype-matched non-immune IgG^[8]. However, since CCL7 receptors are expressed on immune cells, cardiomyocytes and hepatocytes^[56–^57], it is paradoxical that the liver of Mmp2^-/- mice does not exhibit elevated sPLA2 activity, whereas the heart of Mmp2^-/-mice does, compared to wild-type mice. In Box 3 we propose a mechanism that may clarify what makes cardiac sPLA2 "cardiac" in origin.

Influence of the heart-centric MMP-2/CCL7/sPLA2 axis on lipid metabolism

A still-open question is whether MMP-2-mediated proteolysis of cytokines, such as CCL7, perturbs lipid metabolism via CCL7-receptor signaling pathways? To answer this question, Box 4 describes two pathways by which the heart influences hepatic lipid metabolism and inflammation.

Future studies will provide precision to the first pathway described in Box 4, including the molecular identity (amino acid sequence) of the enzyme isoforms responsible for cardiac sPLA2 activity (Box 2) and deciphering the mechanism that regulates the cardiac-specific origin of sPLA2 in MMP-2 deficiency (Box 3).

Conclusions

Some three decades ago, Dr. de Bold and colleagues identified endogenous peptide-hormones (ANP) which they found to stimulate a rapid and massive diuresis and natriuresis when injected in rats. Since this pioneering discovery, which demonstrated directly the endocrine function of the heart, there have been several new discoveries. These include but are not limited to: (i) the identification of other endogenous peptides (e.g., BNP, CNP) with natriuretic and vasodilator activity, (ii) the role of CNPs as hormones that can target various organs (e.g., the liver, brain, pancreas and intestine – not just the kidney) to influence metabolism, (iii) the role of the cardiac-specific miR-208a/MED13 axis to control whole body metabolism, (iv) a MMP-2/CCL7/sPLA2-mediated role played by the heart in inflammation and metabolism. These latter findings are potentially relevant for: (a) Conditions where MMP-2 activity is reduced by inactivating mutations (or polymorphisms) of MMP2 gene or medicinal drugs with MMP-inhibitory actions (although little is known about the prevalence of disorders caused by reduced MMP-2 activity) and (b) Disorders in which the expression of MMPs is deregulated- such as ischemic heart disease, arthritis, cancer, type 2 diabetes, obesity, hypercholesterolemia. Together, these discoveries could be vital for the diagnosis and for the design of new medicines for treating inflammatory and metabolic disorders.

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