Cytokine receptor gp130 promotes postnatal proliferation of cardiomyocytes required for the normal functional development of the heart

Mammalian ventricular cardiomyocytes are premature at birth and exhibit substantial phenotypic changes before weaning. Mouse ventricular myocytes undergo cell division several times after birth; however, the regulatory mechanisms and roles of cardiomyocyte division in postnatal heart development remain unclear. Here, we investigated the physiological role of glycoprotein 130 (gp130), the main subunit of multifunctional receptors for the IL-6 family of cytokines, in postnatal cardiomyocyte proliferation. Pharmacological inhibition of gp130 within the first month after birth induced significant systolic dysfunction of the left ventricle in mice. Consistently, mice with postnatal cardiomyocyte-specific gp130 depletion exhibited impaired left ventricular contractility compared with control mice. In these mice, cardiomyocytes exhibited a moderately decreased size and dramatically inhibited proliferation in the left ventricle but not in the right ventricle. Stereological analysis revealed that this change significantly decreased the number of cardiomyocytes in the left ventricle. Furthermore, IL-6 was mainly responsible for promoting ventricular cardiomyocyte proliferation by activating the JAK/STAT3 pathway. Taken together, the IL-6/gp130/JAK/STAT3 axis plays a crucial role in the physiological postnatal proliferation and hypertrophy of left ventricular cardiomyocytes to ensure normal cardiac functional development. Although cardiomyocytes undergo proliferation in the early postnatal period, the regulatory mechanisms and physiological importance of this process have not been clarified. We found that the pharmacological and genetic depletion of gp130 in preweaning mice resulted in significant impairment of cardiomyocyte proliferation, thinning of the myocardium, and systolic dysfunction of the left but not right ventricle by perturbing JAK/STAT3 signaling. Thus, the IL-6/gp130/JAK/STAT3 axis is crucial for the postnatal functional development of the left ventricle.