Cardiomyocyte remodeling, which includes partial dedifferentiation of cardiomyocytes, is a process that occurs during both acute and chronic disease processes. Here, we demonstrate that oncostatin M (OSM) is a major mediator of cardiomyocyte dedifferentiation and remodeling during acute myocardial infarction (MI) and in chronic dilated cardiomyopathy (DCM). Patients suffering from DCM show a strong and lasting increase of OSM expression and signaling. OSM treatment induces dedifferentiation of cardiomyocytes and upregulation of stem cell markers and improves cardiac function after MI. Conversely, inhibition of OSM signaling suppresses cardiomyocyte remodeling after MI and in a mouse model of DCM, resulting in deterioration of heart function after MI but improvement of cardiac performance in DCM. We postulate that dedifferentiation of cardiomyocytes initially protects stressed hearts but fails to support cardiac structure and function upon continued activation. Manipulation of OSM signaling provides a means to control the differentiation state of cardiomyocytes and cellular plasticity.

Heart failure (HF) is a common and potentially deadly condition, which frequently develops as a consequence of various diseases of the heart. The incidence of heart failure continuously increases in aging societies illustrating the need for new therapeutic approaches. We recently discovered that continuous activation of oncostatin M (OSM), a cytokine of the interleukin-6 family that induces dedifferentiation of cardiomyocytes, promotes progression of heart failure in dilative cardiomyopathy. To evaluate whether inhibition of OSM signaling represents a meaningful therapeutic approach to prevent heart failure we attenuated OSM-receptor (Oβ) signaling in a mouse model of inflammatory dilative cardiomyopathy. We found that administration of an antibody directed against the extracellular domain of Oβ or genetic inactivation of a single allele of the Oβ gene reduced cardiomyocyte remodeling and dedifferentiation resulting in improved cardiac performance and increased survival. We conclude that pharmacological attenuation of long-lasting Oβ signaling is a promising strategy to treat different types and stages of HF that go along with infiltration by OSM-releasing inflammatory cells.

No abstract

Objective-Collateral artery growth or arteriogenesis is the primary means of the circulatory system to maintain blood flow in the face of major arterial occlusions. Arteriogenesis depends on activation of fibroblast growth factor (FGF) receptors, but relatively little is known about downstream mediators of FGF signaling. Methods and Results-We screened for signaling components that are activated in response to administration of FGF-2 to cultured vascular smooth muscle cells (VSMCs) and detected a significant increase of Rap2 but not of other Ras family members, which corresponded to a strong upregulation of Rap2 and C-Raf in growing collaterals from rabbits with femoral artery occlusion. Small interfering RNAs directed against Rap2 did not affect FGF-2 induced proliferation of VSMC but strongly inhibited their migration. Inhibition of FGF receptor-1 (FGFR1) signaling by infusion of a sulfonic acid polymer or infection with a dominant-negative FGFR1 adenovirus inhibited Rap2 upregulation and collateral vessel growth. Similarly, expression of dominant-negative Rap2 blocked arteriogenesis, whereas constitutive active Rap2 enhanced collateral vessel growth. Conclusion-Rap2 is part of the arteriogenic program and acts downstream of the FGFR1 to stimulate VSMC migration.Specific modulation of Rap2 might be an attractive target to manipulate VSMC migration, which plays a role in numerous pathological processes. Key Words: collateral circulation Ⅲ growth factors Ⅲ peripheral arterial disease Ⅲ peripheral vasculature Ⅲ vascular biology C ardiovascular diseases are still the leading cause of death in Western societies, with coronary artery disease being responsible for approximately 50% of this burden. However, the heart of human beings is not defenseless against a slowly occurring closure of artery vessels but responds by collateral arterial growth. This process, which has been termed arteriogenesis, takes place in virtually all organs of the body. It is fundamentally different from angiogenesis in that it relies on the growth of preexisting collateral arterioles and not on the sprouting of capillaries. Arteriogenesis is initiated by shear stress leading to an inflammatory microenvironment and to the activation of growth factor cascades that spur collateral vessel growth and not by hypoxia, which mainly triggers angiogenesis. 1 Furthermore, arteriogenesis is able to completely restore perfusion after occlusion of arteries, whereas angiogenesis improves the local blood supply only marginally, because far too many capillaries would be needed to replace a conducting artery. 2 The ability of arteriogenesis to restore normal blood flow has raised the hope of stimulating this process to combat vascular ischemic diseases. However, the complexity of the regulatory mechanisms driving arteriogenesis, which includes the interplay of different cell types and many growth factors and cytokines, has slowed down therapeutic applications.On the cellular level, arteriogenesis is characterized by dedifferentiation, proliferation, and migra...