Low glial angiotensinogen improves body habitus, diastolic function, and exercise tolerance in aging male rats

Long-term systemic blockade of the renin-angiotensin system (RAS) with either an angiotensin (Ang) II type 1 receptor antagonist or an angiotensin-converting enzyme inhibitor attenuates age-related cardiac remodeling and oxidative damage, and improves myocardial relaxation. However, the role of the brain RAS in mediating the development of diastolic dysfunction during aging is not known. We hypothesized that low brain RAS protects against the development of age-related diastolic dysfunction and left ventricular remodeling.

Sixty-week-old transgenic male ASrAOGEN rats (n =9), with normal circulating Ang II and functionally low brain Ang II, because of a GFAP promoter-linked angiotensinogen antisense targeted to glia, and age-matched and sex-matched Hannover Sprague-Dawley (SD; n= 9) rats, with normal levels of both circulating and brain Ang II, underwent echocardiograms to evaluate cardiac structure and function. Postmortem hearts were further compared for histological, molecular, and biochemical changes consistent with cardiac aging.

ASrAOGEN rats showed preserved systolic and diastolic function at mid-life and this was associated with a lower, more favorable ratio of the phospholamban-SERCA2 ratio, reduced incidence of histological changes in the left ventricle, and increased cardiac Ang-(1-7) when compared with the in-vivo functional, and ex-vivo structural and biochemical indices from age-matched SD rats. Moreover, ASrAOGEN rats had lower percent body fat and a superior exercise tolerance when compared with SD rats of the same age.

Our data indicate that the central RAS plays a role in the maintenance of diastolic function and exercise tolerance in mid-life and this may be related to effects on body habitus.