ANÁLISE DO FENÓTIPO CARDIOVASCULAR DE RATAS TRANSGÊNICAS (TG7371) QUE EXPRESSAM UMA PROTEÍNA DE FUSÃO PRODUTORA DE ANGIOTENSINA-(1-7)

Abstract

Angiotensin-(1-7) [Ang-(1-7)] is an important component of the renin-angiotensin system (RAS) especially for its vasodilator, anti-inflammatory, and anti-proliferative properties. It is considered an endogenous counterregulatory peptide of the vasoconstrictor and proliferative effects of Angiotensin II (Ang II). As a result of their physiological role in controlling blood pressure (BP) and hydroelectrolytic balance, as well as their participation in the pathophysiology of cardiovascular diseases, RAS components have been targets for the development of transgenic animals. In the present study, we compared the cardiovascular phenotype of females of a new strain of transgenic rats, the TG(A-7)-L7371 (TG), with males of same strain. This TG express a gene that encodes a fusion protein containing the Ang-(1-7) sequence, and which is associated with a specific promoter, the human glial acidic fibrillar protein (hGFAP). For this study, male and female Sprague Dawley rats (SD; control group) and TG rats were used. Systolic blood pressure (SBP) was measured non-invasively by tail plethysmography. In females, the SBP measurement was associated with the assessment of the different phases of the estrous cycle. Mean arterial pressure (MAP) and heart rate (HR) were also evaluated by direct measurement through cannulation of the femoral artery coupled to the Biopac System recording system. The sensitivity of the baroreflex control for the bradycardic component was evaluated, through HR variations resulting from increases in MAP induced by intravenous injection of phenylephrine. Cardiac autonomic tone was determined through sequential and alternating blockade of β-adrenergic receptors, with propranolol and muscarinics, with methyl-atropine. Circulating angiotensin levels were measured in plasma by mass spectrometry. Results obtained in the present study showed: 1) Female and male TG rats showed lower levels of BP than SD, both by tail plethysmography and by direct short-term recordings; 2) Females, both SD and TG, had lower BP levels than males of their respective lineages; 3) No significant differences were observed in SBP during the different phases of the estrous cycle; 4) TG females showed an increase in HR compared to SD females and TG males; 5) TG females showed baroreflex HR control sensitivity identical to SD females, however, higher compared to TG males; 6) Both TG females and males showed plasma concentrations of Ang-(1-7) similar to the respective SD controls; 8) TG and SD females showed increased levels of Ang-(1-7) compared to males of their respective strains; 9) SD females also showed increased levels of Ang I and Ang II compared to SD males. These results suggest that overexpression of tissue Ang-(1-7) can induce beneficial effects on the cardiovascular system, such as BP reduction. Considering that the genetic background is from a normotensive animal, this is a very relevant result and makes this animal an interesting model to study the effect of long-term tissue increase of Ang-(1-7) on the pathophysiology and treatment of cardiovascular disease, especially in females.