Physiopathology and molecular mechanisms of cardiometabolic remodeling
Obesity-related cardiac remodeling is associated with dysregulation of several peptide-secreting systems. The main focus of our work is to understand how cardiac cells respond to bioactive factors to contribute to remodeling processes, and thereby to heart adaptation or disease. Our most recent research has centered on the role of two biologically active peptides, apelin and galanin.
Apelin is produced by the adipose tissue and plays an important and beneficial role in regulating cardiovascular and metabolic homeostasis. Previously, we have shown that apelin prevents oxidative stress and hypertrophic responses in cardiac cells. We have also explored the role of apelin in cardiac fibroblast activation in response to cardiac remodeling. Our data suggest that apelin prevents activation of pro-fibrotic cascades and preserves left ventricular function in heart failure. In high-fat diet-induced obesity, we have recently demonstrated that the transition from compensated hypertrophy to heart failure is characterized by defective myocardial energy metabolism and mitochondrial defects. Furthermore, apelin is able to prevent such myocardial metabolic abnormalities and mitochondrial dysfunction.
Looking for the molecular mechanisms underlying the protective effects of apelin in the heart, we revealed a key role of apelin in the regulation of Forkhead Box O (FoxO) transcription factors governing cellular responses to oxidative stress. We have provided in vitro and in vivo evidence that apelin controls the nucleo-cytosolic shuttling of FoxO1/FoxO3 in response to oxidative cardiac damage. In a mouse model combining cardiac ischemia-reperfusion (I/R) injury and high-fat diet-induced obesity, we showed that post-reperfusion treatment with apelin attenuates mitochondrial ROS production and cardiac cell apoptosis via FoxO1/FoxO3 activation. Finally, in order to translate the basic results to clinical investigation, we have examined the circulating level of apelin in obese and lean patients with ischemic cardiomyopathy (collaboration with Pr. J. Roncalli, Department of Cardiology, Toulouse University Hospital. We show that elevated circulating apelin is correlated with improved cardiac fonction in obese patients with heart failure.
Stabilization of peptide-based drug products represents a significant therapeutic challenge. In order to develop physiologically stable peptide analogues, we have initiated an interdisciplinary collaborative project with Pisarenko’s group from the Russian Cardiology Research-and-Production Complex (Moscow) to designe proteolytic resistant and chemical stable analogues of apelin. We demonstrated that these compounds selectively inhibit hypoxia-induced mitochondrial ROS production and preserve metabolic status after reperfusion injury on isolated rat hearts. Our data suggest that structural apelin analogues may represent a promising new strategy for the management of ischemic heart disease.
Our interest for galanin is more recent but gave already very promising results. Galanin is a bioactive peptide hormone that regulates the numerous physiological processes such as food intake, memory, the neuroendocrine function, gut secretion, and motility. Like apelin, galanin is a small peptide (29- to 30-residues) widely distributed in the central and peripheral nervous system and is expressed abundantly in the heart. In the cardiovascular system, galanin has important vasoactive effects and galanin expression is elevated significantly in cardiac sympathetic neurons after myocardial infarction. More recent study has reported that galanin may directly affect glucose metabolism in cardiac and skeletal muscles suggesting that the galaninergic system may play an important role in metabolic and cardiovascular homeostasis. Unlike apelin, for which the role in prevention of ROS-dependent oxidative damage has been reported by our group, the potential role of galanin in the regulation of ROS production in obesity-related heart disease remains to be defined.
The direction of our research is driven by three specific objectives:
1) to determine the role of bioactive peptides in the regulation of cardiac remodeling processes during the transition from hypertrophy to heart failure in obesity
2) to delineate the cellular and molecular mechanisms governing cardiac cell responses to bioactive peptides in obesity-related myocardial remodeling
3) to develop new preventive and therapeutic strategies for obesity-related cardiometabolic complications.