Dhamrait, S.S. (2010) Angiotensin converting enzyme and mitochondria – molecular and genetic mechanisms involving bradykinin receptors and uncoupling proteins. Doctoral thesis, UCL (University College London).
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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.
|Title:||Angiotensin converting enzyme and mitochondria – molecular and genetic mechanisms involving bradykinin receptors and uncoupling proteins|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of) > Cardiovascular Medicine|
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