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Epicardial adipose tissue as a regulator of myocardial biology: adiponectin signaling pathways

Final Report Summary - HRS EAT (Epicardial adipose tissue as a regulator of myocardial biology: adiponectin signaling pathways)

Summary Description of the Project Objectives
The Project had set as an aim a) To investigate the direct / paracrine effects of adiponectin released from epicardial adipose tissue (EpAT) on myocardial redox state in humans, b) To examine the effects of adiponectin on myocardial contractility, c) to search for a possible paracrine signal from the myocardium to epicardial AT that could modify adiponectin synthesis, d) to determine the critical downstream signaling pathways in human heart, responsible for the possible effect of adiponectin on myocardial redox state in the human heart.

Description of the work performed since the beginning of the project
The Project was designed (Figure 1 - see attachment) to run in three parallel arms. In Study Arm 1 patients undergoing coronary artery bypass grafting (CABG, n=251) were recruited in order to build a bioresource of adipose and myocardial tissue samples and to search for clinical associations between AT expression of adiponectin and myocardial redox state in humans (months 1-20). In Study Arm 2, samples of myocardium and AT were collected from 55 additional CABG patients and used in ex vivo experiments to address the mechanisms regulating the interactions between AT and the heart (months 6-18). In Study Arm 3, a transgenic mouse model of increased myocardial oxidative stress was used to further validate the clinical observations made (months 18-22). Successful completion of all study arms required multidisciplinary training in clinical research skills, clinical imaging techniques (cardiac ultrasound and computed tomography), mendelian randomisation strategies, ex vivo human tissue models (AT culture bioassays, myocardial contractility experiments, assessment of myocardial redox state) as well as cell culture and aspects of animal work.

Description of the main results
The Project has yielded important novel findings.
Finding A: Biosynthesis of adiponectin by human adipose tissue is determined by the reciprocal effects of natriuretic peptides and systemic inflammation. In patients with ischemic heart disease plasma natriuretic peptides globally increase adiponectin biosynthesis from AT and counteract the deleterious effects of systemic inflammation, locally, on femoral fat. These findings have shed more light on the complex mechanisms regulating adiponectin biosynthesis in human AT.
Finding B: Higher myocardial oxidative stress is associated with higher adiponectin biosynthesis in human epicardial AT. At the level of clinical cohort, there was a positive association between plasma adiponectin and myocardial NADPH oxidase activity, independently of natriuretic peptides or classic risk factors. This association was stronger when looking into the expression of adiponectin from epicardial AT, but lost when looking at fat depots distal to the heart e.g. thoracic AT. This was a paradoxical finding given the well-described antioxidant effects of adiponectin in cell cultures and animal models.
Finding C: Adiponectin has antioxidant effects on human myocardium by reducing NADPH-oxidase activity. To explain “Finding B”, we employed a mendelian randomisation approach by using two functional single nucleotide polymorphisms of ADIPOQ gene (encoding adiponectin) we demonstrated that genetically conferred increases in plasma/epicardial AT adiponectin are associated with lower myocardial NADPH oxidase superoxide generation. Moreover, in ex-vivo incubations of human myocardium with recombinant human adiponectin, it was demonstrated, for the first time in humans, that adiponectin-induced activation of AMPK signalling attenuates Rac1 activation and p47phox phosphorylation and their membrane translocation, and thus reduces myocardial NADPH oxidase activity.
Finding D: Human heart regulates epicardial adipose tissue biology. Finding B and C implied that there might be a signal originating from the heart inducing adiponectin biosynthesis in epicardial AT. In a series of ex-vivo mechanistic experiments with human AT, we provided first proof of an “inside-to-outside” signal from the heart to epicardial adipose tissue. Increased myocardial NADPH oxidase activity leads to formation of lipid oxidation products; a lipid oxidation product, 4-hydroxynonenal or one of its adducts, induces peroxisome proliferator-activated receptor (PPAR)-γ activation in human epicardial AT, which increases adiponectin expression. This finding was also validated by using a cardiomyocyte-specific Nox2 transgenic mouse model, as a model of increased myocardial oxidative stress; increased myocardial NADPH oxidase activity led to increased adiponectin expression in the fat attached to the mouse heart but not in remote fat depots.
Conclusions: Taken together Findings A-B, provide evidence, for the first time in humans, of the bidirectional interactions between epicardial adipose tissue and the human heart that regulate myocardial NADPH oxidase activity through PPAR-γ/adiponectin signalling (Figure 2 - see attachment).

Expected final results and their potential impact and use
To date epicardial AT fat was understood as a fat pad, surrounding the heart, reflecting total obesity burden. Adipokines-secreted by epicardial fat can affect heart biology, but a thorough understanding of the underlying mechanisms involved in this process. The Project demonstrated, for the first time in humans, that the interactions between epicardial fat and the heart are not unidirectional, but rather bidirectional; by employing a translational approach we provided first evidence in humans for the crosstalk between the heart and epicardial fat; it was highlighted that in the presence of advanced myocardial disease, the heart transmits signals that are “sensed” by epicardial AT, and the latter responds by upregulating the expression of protective genes (e.g. adiponectin), as a defensive mechanism against myocardial disease. The study findings may have important implications, since this crosstalk between epicardial AT and the human heart could constitute a rational therapeutic target. Targeted overexpression of PPAR-γ signalling and/or adiponectin in epicardial fat could have beneficial antioxidant effects on the failing myocardium of ischemic heart disease patients.