Renin-angiotensin system is involved in homeostasis processes linked to renal and cardiovascular system and recently has been linked to metabolic syndrome. We analyzed the influence of long term angiotensin I converting enzyme (ACE) inhibitor enalapril treatment in normotensive adult Wistar rats fed with standard or palatable hyperlipidic diets. Our results show that long term enalapril treatment decreases absolute food intake, serum leptin concentration and body weight gain. Moreover, in adipose tissue, enalapril treatment led to decreased ACE activity, enhanced the expression of peroxisome proliferator activated receptor gamma, adiponectin, hormone-sensitive lipase, fatty acid synthase, catalase and superoxide dismutase resulting in prolonged life span. On the other hand, the ACE inhibitor was not able to improve the transport of leptin through the blood brain barrier or to alter the sensitivity of this hormone in the central nervous system. The effect of enalapril in decreasing body weight gain was also observed in older rats. In summary, these results extend our previous findings and corroborate data from the literature regarding the beneficial metabolic effects of enalapril and show for the first time that this ACE inhibitor prolongs life span in rats also fed with palatable hyperlipidic diet, an action probably correlated with adipose tissue metabolic modulation and body weight reduction.

Muscle damage is one of the most important factors that affect muscle fatigue during endurance exercise. Recent evidence suggests that the renin–angiotensin system impacts on skeletal muscle wasting. The aim of this study was to determine association between the AGT Met235Thr, ACE I/D and BDKRB2 −9/+9 polymorphisms with inflammation, myocardial and muscle injury induced by endurance exercise. Eighty-one Brazilian male runners participated in this study and completed the International Marathon of Sao Paulo. Muscle and myocardial damage markers (alanine transaminase, ALT, aspartate transaminase, AST, lactic dehydrogenase, LDH, creatine kinase, CK, Troponin, pro BNP, myoglobin, and CK-MB) and inflammatory mediators (IL-6, IL-8, IL-10, IL12p70, IL1β, and TNF-α) were determined one day before, immediately after, one day after, and three days after the event. Muscle damage was also determined fifteen days after race and angiotensinogen (AGT) Met235Thr, angiotensin-converting enzyme (ACE) I/D, and Bradykinin B2 receptor (BDKRB2) −9/+9 polymorphisms were determined. Marathon race participation induced an increase in all muscle damage and inflammatory markers evaluated (p < 0.0001). The muscle damage markers, troponin and pro BNP, CK and LDH and inflammatory markers, IL-6, IL-8, IL-1β and IL-10 were also higher in ACE II genotype immediately after race, compared to DD genotype. The percentage of runners higher responders (>500U/I) to CK levels was higher for II genotypes (69%) compared to DD and ID genotypes (38% and 40%, respectively) immediately after. Troponin, pro BNP and IL-1β, IL-8 levels were also elevated in AGT MM genotype compared to TT genotype athletes after and/or one day after race. BDKRB2 −9/−9 had pronounced response to LDH, CK, CK-MB and ALT and AST activities, myoglobin, troponin, IL-6, IL-8 levels immediately, one day and/or three days after race. The percentage of runners higher responders (>500U/I) to CK levels was greater for −9−9 and −9+9 genotypes (46 and 48%, respectively) compared to +9+9 genotypes (31%) immediately after. ACE II, AGT MM, and BDKRB2 −9−9 genotypes may increase the susceptibility to inflammation, muscle injury after endurance exercise and could be used to predict the development of clinical conditions associated with muscle damage and myocardial injury.

Fabry disease is a multisystem X-linked disorder resulting from α-galactosidase A (α-GalA) gene mutations leading to the accumulation of globotriaosylceramide mainly in endothelium compromising heart, kidney, and brain. In Fabry patients, progressive renal failure is frequently treated with angiotensin I-converting enzyme (ACE) inhibitors. We were interested in the possible interactions between ACE inhibitors therapy and the only causative therapy for Fabry disease, the enzyme replacement therapy (ERT) using recombinant human α-GalA (rhα-GalA). Our results suggest that ACE activity was significantly inhibited in plasma of Fabry patients and the blood pressure level decreased just after ERT (at the end of the rhα-GalA infusion). Interestingly, 2 weeks later, ACE activity was significantly upregulated and the plasma levels of angiotensin II increased in the patients treated with rhα-GalA following the elevations of ACE activity. The same inhibitory effect on ACE activity was also observed in rats after rhα-GalA infusion. Furthermore, ACE activity in CHO cells transfected with the human ACE was inhibited dose and time-dependently by rhα-GalA. In vitro, the incubation of plasma from healthy volunteers with rhα-GalA significantly reduced ACE activity. Finally, rhα-GalA also inhibited ACE activity and released galactose residues from purified rabbit lung ACE dose-dependently. In summary, our results suggest that rhα-GalA interacts with ACE and inhibits its activity, possibly by removing the galactose residues from the enzyme. This modulation might have profound impact on the clinical outcome of Fabry patients treated with rhα-GalA.

Segregation analysis is important in order to confirm the molecular diagnosis of patients with Stargardt disease, given the frequency of complex alleles in the ABCA4 gene. The various pathogenic variation combinations observed in this study were associated with different phenotypes.

Hereditary angioedema (HAE) is accompanied by an overproduction of bradykinin (BK) as the primary mediator of swelling. Although many proteins may be involved in regulating the wide spectrum of HAE symptoms, most studies have only focused on C1-INH and FXII. For the first time, a next generation sequencing (NGS) method was applied to develop a robust, time- and cost-effective diagnostic and research tool to analyze selected genes related to HAE. The entire coding region and the exon-intron boundaries of 15 genes from 23 subjects of a Brazilian family, nine of whom were symptomatic, were analyzed by NGS. One new mutation found uniquely in the nine symptomatic patients, p.Ala457Pro in the SERPING1 gene, was estimated as likely to be pathogenic (PolyPhen-2 software analysis) and is the main candidate to be responsible for HAE in these patients. Alterations identified in a few asymptomatic individuals but also found in almost all symptomatic patients, such as p.Ile197Met (HMWK), p.Glu298Asp (NOS3) and p.Gly354Glu (B2R), may also be involved in modulating patient-specific symptoms. This NGS gene panel has proven to be a valuable tool for a quick and accurate molecular diagnosis of HAE and efficient to indicate modulators of HAE symptoms.