Complement 5a Receptor deficiency does not influence adverse cardiac remodeling after pressure-overload in mice

Judith J De Haan,Dominique P V De Kleijn,Marissa Bastemeijer,Joost P G Sluijter,Anouska Borgman,Sander M Van De Weg,Lena Bosch,Saskia C A De Jager,Maike A D Brans,Hamid El Azzouzi

doi:10.1038/s41598-017-16957-3

Judith J De Haan, Dominique P V De Kleijn + Show 8 more

Open Access

https://doi.org/10.1038/s41598-017-16957-3

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Abstract

Hypertension is one of the most common risk factors for the development heart failure in the general population. Inflammation plays a central role in this adverse remodeling and eventually to the development of heart failure. Circulating levels of Complement factor 5a (C5a) are increased in hypertensive patients and the C5a receptor is associated with the presence of cardiac fibrosis and inflammation in an experimental hypertension model. To test if C5aR is involved in adverse cardiac remodeling following pressure-overload, we induced transverse aortic constriction (TAC) in wildtype and C5a receptor deficient mice (C5aR−/−). Six weeks after TAC, C5aR-/- animals showed a similar degree of cardiac hypertrophy and decrease in cardiac function as wild type mice (End Systolic Volume; 50.30±5.32 µl vs. 55.81±8.16 µl). In addition, other features of adverse cardiac remodeling like cardiomyocyte cell size (WGA staining), fibrosis (picrosirius red staining) or collagen degradation (matrix metalloproteinase activity assay) did not differ either. In conclusion, full body C5aR deficiency does not affect adverse cardiac remodeling after pressure-overload. However, our finding are in contrast with C5a inhibition studies. Our observations do present the role of C5a-C5aR in adverse cardiac remodeling and heart failure as controversial at the least.

Highlights

Heart failure (HF) is a growing major worldwide clinical problem and it has a poor 5-year survival[1]
Survival, cardiac hypertrophy, and cardiac function are comparable between week of TAC (WT) and C5a receptor (C5aR)−/− mice following transverse aortic constriction (TAC)
To study if matrix remodeling was affected by the absence of C5aR, we looked at the mRNA levels of collagen and the activity of Matrix Metalloproteinases (MMPs)

Summary

Introduction

Heart failure (HF) is a growing major worldwide clinical problem and it has a poor 5-year survival[1]. Hypertension is one of the most common risk factors for the development of HF It has a high prevalence, 75–91% of HF cases had prior hypertension and the attributable risk for HF is accounted by hypertension in 59% in women and 39% in men in the Framingham Heart Study and Framingham Offspring Study[2,3]. In patients this chronical hypertension leads to adverse remodeling of the myocardium. We hypothesized that deficiency of C5aR would ameliorate pressure-overloaded adverse cardiac remodeling induced by transverse aortic constriction (TAC), accompanied by a reduced inflammatory and fibrotic response. C5aR knock-out (C5aR−/−) and wild type mice were subjected to TAC for 6 weeks and cardiac function was assessed by echocardiography, followed by histological analyses

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