Cardiac remodeling in eNOS deficient mice modulated by adiponectin levels

Abstract

With a focus on cardiac remodeling and metabolic disorders, we applied cardiac MRI, among other monitoring techniques, in a serial non-invasive study in mouse models. Our interest in the therapeutic potential of endothelial nitric oxide synthase (eNOS) and adiponectin (APN), lead us to investigate how variations of plasma APN impact on the detrimental effects of eNOS deficiency, combining hypertension and stress with high fat/high cholesterol feeding (HFD) as main variables. We bred two novel mice lacking eNOS, APN was absent (KO-KO) in one and was over-expressed (TG-KO) in the other.;Our results indicate that the effect of HFD on bodyweight (BW) and fat mass gain was more extensive in male than female mice. BW increased the most in mice over-expressing APN. Mice lacking both APN and eNOS gained BW at a similar rate as control wildtype mice suggesting that the concomitant absence of both APN and eNOS may predispose the mice to obesity.;Cardiac hypertrophy seems to be modulated by level of expression of APN, leading to two divergent types of cardiac dysfunction. The cardiomyopathy observed in mice lacking both APN and eNOS is associated with diastolic dysfunction and loss of relaxation properties, whereas male mice lacking eNOS and over-expressing APN had bigger hearts with more dilated chambers, suggesting systolic dysfunction and challenged contractility. Over-expression of APN provided some protection from hypertension in mice lacking eNOS. Although this compensatory effect was diminished with age it suggests the existence of eNOS-independent mechanisms to partially rescue the hypertensive phenotype. Our data also suggests that there is an optimal range of expression of APN for cardio-protection and that too much or too little APN might be detrimental. In addition, mice lacking eNOS had higher plasma APN levels than wildtype mice, suggesting upregulation of APN to compensate for the lack of eNOS.;In conclusion, APN is more efficient as a cardioprotective agent in the presence of eNOS although, when over-expressed, APN might be detrimental, especially in terms of cardiac remodeling and dysfunction. This may open a new channel of therapeutic strategies based on the metabolic actions and interactions of eNOS and APN.