Angiotensin converting enzyme and mitochondria – molecular and genetic mechanisms involving bradykinin receptors and uncoupling proteins

Low angiotensin converting enzyme (ACE) activity is associated with various cardiovascular phenotypes including reduced left ventricular (LV) hypertrophy, reduced cardiovascular events and enhanced metabolic efficiency, but precise mechanisms are unclear and direct genetic associations remain controversial. ACE degrades kinins and promotes formation of angiotensin II. Combined genetic and in vitro studies were used to test the hypothesis that the previously observed effects may be through alterations in kinins or mitochondrial function via novel uncoupling proteins (UCPs). The -9 allele of the bradykinin β2 receptor BDKRB2+9/-9 gene variant is correlated with low kinin activity and was associated with lower prospective LV growth during strenuous physical exercise and lower prospective hypertensive cardiovascular risk, as well as increased efficiency of skeletal muscle contraction (delta efficiency) in healthy volunteers (P = 0.003, accounting for 11% of the inter-individual variability). Addition of angiotensin II to skeletal myocytes resulted in a 3.5 fold increase in oxygen consumption (P = 0.03). Incubation of isolated myocytes with an ACE inhibitor lead to mitochondrial membrane hyperpolarisation, suggesting mitochondrial coupling may be an important mediator of the cellular actions of ACE. A common promoter variant in the UCP2 gene was associated with a two-fold increase in prospective cardiovascular risk (P < 0.0001). Variation in the UCP3/2 gene cluster accounted for 15% of the inter-individual endurance training related changes in delta efficiency and there was a surprising, but consistent, association with serum ACE activity. Finally, in vitro assays confirmed physiological downregulation of UCP2 in endothelial cells was associated with increased oxidative stress and reduced ACE mRNA. In conclusion, BDKRB2 may mediate some of the beneficial metabolic and cardiovascular effects associated with low ACE activity, possibly through changes in mitochondrial function. Mitochondrial coupling appears pivotal in cardiovascular (patho)physiology, possibly via oxidative stress or a novel ACE metabolic regulatory pathway. UCPs may be a target for future cardiovascular interventions

Association between plasma activities of semicarbazide-sensitive amine oxidase and angiotensin-converting enzyme in patients with type 1 diabetes mellitus

Aims/hypothesis: Plasma semicarbazide-sensitive amine oxidase (SSAO) is elevated in patients with type 1 and type 2 diabetes and has been implicated in the pathophysiology of diabetic late complications. The regulation of SSAO production remains unknown. We studied correlations between plasma SSAO activity and parameters associated with diabetic late complications. Methods: Plasma SSAO was measured in a well-characterised group of 287 patients with type 1 diabetes. Standard statistical methods were used to investigate correlations with clinical parameters and components of the renin-angiotensin system. Results: Overall, plasma SSAO was elevated, at 693±196 mU/l (mean±SD; normal controls 352±102 mU/l). Plasma SSAO was higher in the group with late complications or hypertension, and in patients treated with ACE-inhibitors. In univariate analysis a significant positive correlation (p<0.001, r=0.27) was found between plasma SSAO and serum ACE activity in patients untreated with ACE inhibitors or angiotensin II receptor antagonists (n=221), but plasma SSAO did not differ by ACE I/D genotype. Plasma SSAO correlated positively with duration of diabetes, HbA1c and plasma renin, and negatively with plasma angiotensinogen and body mass index. A multiple regression analysis including these variables resulted in serum ACE activity (p<0.001), ACE genotype (negatively, p<0.001) and HbA 1c (p=0.023) as explaining variables. Conclusions/interpretation: Results suggest that a common factor is involved in the regulation of both plasma SSAO and serum ACE, which is different from the genetic determination of ACE activity

Genetic variation and activity of the renin-angiotensin system and severe hypoglycemia in type 1 diabetes

BACKGROUND: The deletion-allele of the angiotensin-converting enzyme (ACE) gene and elevated ACE activity are associated with increased risk of severe hypoglycemia in type 1 diabetes. We explored whether genetic and phenotypic variations in other components of the renin-angiotensin system are similarly associated. METHODS: Episodes of severe hypoglycemia were recorded in 171 consecutive type 1 diabetic outpatients during a 1-year follow-up. Participants were characterized at baseline by gene polymorphisms in angiotensinogen, ACE, angiotensin-II receptor types 1 (AT1R) and 2 (AT2R), and by plasma angiotensinogen concentration and serum ACE activity. RESULTS: Three risk factors for severe hypoglycemia were identified: plasma angiotensinogen concentration in the upper quartile (relative rate [RR] vs. lower quartile 3.1, 95% confidence interval [CI,] 1.4-6.8), serum ACE activity in the upper quartile (RR vs. lower quartile 2.9, 95% CI, 1.3-6.2), and homo- or hemizygosity for the A-allele of the X chromosome-located AT2R 1675G/A polymorphism (RR vs. noncarriers 2.5, 95% CI, 1.4-5.0). The three risk factors contributed independently to prediction of severe hypoglycemia. A backward multiple regression analysis identified a high number of renin-angiotensin system-related risk factors and reduced ability to perceive hypoglycemic warning symptoms (impaired hypoglycemia awareness) as predictors of severe hypoglycemia. CONCLUSIONS: High renin-angiotensin system activity and the A-allele of the AT2R 1675G/A polymorphism associate with high risk of severe hypoglycemia in type 1 diabetes. A potential preventive effect of renin-angiotensin system blocking drugs in patients with recurrent severe hypoglycemia merits further investigation

The Belgian Competition Council rejects a complaint of abuse of dominance in the beer distribution sector (Inbev)

10.1186/1475-2840-8-31Cardiovascular Diabetology83