Overexpression Of Endothelial Beta(3)-Adrenergic Receptor Induces Diastolic Dysfunction In Rats

Aims Diastolic dysfunction is common in cardiovascular diseases, particularly in the case of heart failure with preserved ejection fraction. The challenge is to develop adequate animal models to envision human therapies in the future. It has been hypothesized that this diastolic dysfunction is linked to alterations in the nitric oxide ((NO)-N-center dot) pathway. To investigate this issue further, we investigated the cardiac functions of a transgenic rat model (Tg beta(3)) that overexpresses the human beta(3)-adrenoceptor (h beta(3)-AR) in the endothelium with the underlying rationale that the (NO)-N-center dot pathway should be stimulated in the endothelium.Methods and results Transgenic rats (Tg beta(3)) that express h beta(3)-AR under the control of intercellular adhesion molecule 2 promoter were developed for a specific expression in endothelial cells. Transcriptomic analyses were performed on left ventricular tissue from 45-week-old rats. Among all altered genes, we focus on (NO)-N-center dot synthase expression and endothelial function with arterial reactivity and evaluation of (NO)-N-center dot and O(2)(center dot-)production. Cardiac function was characterized by echocardiography, invasive haemodynamic studies, and working heart studies. Transcriptome analyses illustrate that several key genes are regulated by the h beta(3)-AR overexpression. Overexpression of h beta(3)-AR leads to a reduction of Nos3 mRNA expression (-72%; P < 0.05) associated with a decrease in protein expression (-19%; P < 0.05). Concentration-dependent vasodilation to isoproterenol was significantly reduced in Tg beta(3)aorta (-10%; P < 0.05), while(center dot)NO and O(2)(center dot-)production was increased. In the same time, Tg beta(3)rats display progressively increasing diastolic dysfunction with age, as shown by an increase in the E/A filing ratio [1.15 +/- 0.01 (wild type, WT) vs. 1.33 +/- 0.04 (Tg beta(3)); P < 0.05] and in left ventricular end-diastolic pressure [5.57 +/- 1.23 mmHg (WT) vs. 11.68 +/- 1.11 mmHg (Tg beta(3)); P < 0.05]. In isolated working hearts, diastolic stress using increasing preload levels led to a 20% decrease in aortic flow [55.4 +/- 1.9 mL/min (WT) vs. 45.8 +/- 2.5 mL/min (Tg beta(3));Conclusions The Tg beta(3) rat model displays the expected increase in (NO)-N-center dot production upon ageing and develops diastolic dysfunction. These findings provide a further link between endothelial and cardiac dysfunction. This rat model should be valuable for future preclinical evaluation of candidate drugs aimed at correcting diastolic dysfunction.