Signaling via the Interleukin-10 Receptor Attenuates Cardiac Hypertrophy in Mice During Pressure Overload, but not Isoproterenol Infusion.

Nicholas Stafford,Min Zi,Delvac Oceandy,Elizabeth J Cartwright,Sukhpal Prehar,Ana M De Morais,Werner Mueller,Arfa Maqsood,Farryah Assrafally

doi:10.3389/fphar.2020.559220

Abstract

Inflammation plays a key role during cardiac hypertrophy and the development of heart failure. Interleukin-10 (IL-10) is a major anti-inflammatory cytokine that is expressed in the heart and may play a crucial role in cardiac remodeling. Based on the evidence that IL-10 potentially reduces pathological hypertrophy, it was hypothesized that signaling via the IL-10 receptor (IL10R) in the heart produces a protective role in reducing cardiac hypertrophy. The aim of this study was to investigate the effects of the ablation of Il-10-r1 gene during pathological cardiac hypertrophy in mice. We found that IL-10R1 gene silencing in cultured cardiomyocytes diminished the anti-hypertrophic effect of Il-10 in TNF-α induced hypertrophy model. We then analyzed mice deficient in the Il-10-r1 gene (IL-10R1-/- mice) and subjected them to transverse aortic constriction or isoproterenol infusion to induce pathological hypertrophy. In response to transverse aortic constriction for 2 weeks, IL-10R1-/- mice displayed a significant increase in the hypertrophic response as indicated by heart weight/body weight ratio, which was accompanied by significant increases in cardiomyocyte surface area and interstitial fibrosis. In contrast, there was no difference in hypertrophic response to isoproterenol infusion (10 days) between the knockout and control groups. Analysis of cardiac function using echocardiography and invasive hemodynamic studies did not show any difference between the WT and IL-10R1-/- groups, most likely due to the short term nature of the models. In conclusion, our data shows that signaling via the IL-10 receptor may produce protective effects against pressure overload-induced hypertrophy but not against β-adrenergic stimuli in the heart. Our data supports previous evidence that signaling modulated by IL-10 and its receptor may become a potential target to control pathological cardiac hypertrophy.

Highlights

Heart failure remains one of the primary causes of morbidity and mortality across the global spectrum of cardiovascular disease
To investigate whether IL-10 exerts its function through activation of the IL-10 receptor (IL-10R), we generated adenovirus expressing shRNA to inhibit the expression of the IL-10R1 gene encoding the main sub-unit of the receptor, in isolated neonatal rat cardiomyocytes (NRCM)
In IL-10R1 deficient cardiomyocytes, TNF-α on its own was able to induce hypertrophy, treatment with IL-10 failed to reduce the hypertrophic effect (Figures 1B,C). This finding suggests that IL-10 mediated signaling in cardiomyocytes is important in repressing the hypertrophic effect of TNF-α, and sufficient expression of the IL-10R1 gene is required for this effect

Summary

Introduction

Heart failure remains one of the primary causes of morbidity and mortality across the global spectrum of cardiovascular disease. Despite current advances in the therapeutic approach, prognosis of this disease remains poor and its prevalence is rising (Mozaffarian et al, 2015; Taylor et al, 2017). Understanding the pathophysiology of heart failure is essential for the development of effective and efficient new therapeutic approaches. Almost all primary myocardial injuries such as pressure overload and ischemia can trigger activation of the immune response. Molecules that are released by damaged myocytes, for example heat shock proteins, fibronectins and reactive oxygen species, may activate residential macrophages and other immune cells, which eventually triggers the release of inflammatory cytokines (Mann, 2015)

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