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Review
. 2012 Mar 1;302(5):R510-7.
doi: 10.1152/ajpregu.00512.2011. Epub 2011 Dec 14.

Intracardiac intracellular angiotensin system in diabetes

Rajesh Kumar  1 , Qian Chen Yong, Candice M Thomas, Kenneth M Baker
Affiliations
Review

Intracardiac intracellular angiotensin system in diabetes

Rajesh Kumar et al. Am J Physiol Regul Integr Comp Physiol. .

Abstract

The renin-angiotensin system (RAS) has mainly been categorized as a circulating and a local tissue RAS. A new component of the local system, known as the intracellular RAS, has recently been described. The intracellular RAS is defined as synthesis and action of ANG II intracellularly. This RAS appears to differ from the circulating and the local RAS, in terms of components and the mechanism of action. These differences may alter treatment strategies that target the RAS in several pathological conditions. Recent work from our laboratory has demonstrated significant upregulation of the cardiac, intracellular RAS in diabetes, which is associated with cardiac dysfunction. Here, we have reviewed evidence supporting an intracellular RAS in different cell types, ANG II's actions in cardiac cells, and its mechanism of action, focusing on the intracellular cardiac RAS in diabetes. We have discussed the significance of an intracellular RAS in cardiac pathophysiology and implications for potential therapies.

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Figures

Fig. 1.
Fig. 1.
Intracellular ANG II in adult mouse cardiac myocytes. Cardiac myocytes were isolated from young adult mice using the Langendorff method. Myocytes were grown in medium containing normal glucose (NG; 5.5 mM), high glucose (HG; 25 mM), or HG + candesartan (Cand; 1 μM). After 24 h, cells were coimmunostained for ANG II (green) and α-sarcomeric actin (red) and visualized with a confocal microscope. A high degree of intracellular ANG II staining (yellow) was observed in HG medium compared with NG. Candesartan did not have any effect on levels of intracellular ANG II, suggesting intracellular synthesis.
Fig. 2.
Fig. 2.
Sources of intracellular ANG II in cardiomyocytes. A, internalization: ANG II-AT1 receptor complex undergoes internalization in the process of cellular signaling. The complex dissociates intracellularly, resulting in the degradation or release of ANG II in the cytoplasm. B, high-glucose stimulation: intracellular synthesis following stimulation with high glucose. The precise intracellular site of ANG II synthesis is not known; however, it appears to occur outside of the secretory pathway. In cardiomyocytes, renin and chymase are involved in intracellular ANG II synthesis. C, isoproterenol stimulation: intracellular synthesis following stimulation with isoproterenol: In this case, ANG II synthesis likely occurs inside the secretory vesicles, due to cosorting of AGT, renin, and ACE. Part of the secretory vesicle ANG II content is released into the cytoplasm, while what remains is secreted outside of the cell. Cytoplasmic ANG II can freely diffuse into nucleus due to the small size. ANG II likely has multiple interaction sites in the cytoplasmic organelles and nucleus.
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References

    1. Ahmad S, Varagic J, Westwood BM, Chappell MC, Ferrario CM. Uptake and metabolism of the novel peptide angiotensin-(1–12) by neonatal cardiac myocytes. PLoS One 6: e15759, 2011 - PMC - PubMed
    1. Bader M. Tissue renin-angiotensin-aldosterone systems: Targets for pharmacological therapy. Annu Rev Pharmacol Toxicol 50: 439–465, 2010 - PubMed
    1. Baker KM, Chernin MI, Schreiber T, Sanghi S, Haiderzaidi S, Booz GW, Dostal DE, Kumar R. Evidence of a novel intracrine mechanism in angiotensin II-induced cardiac hypertrophy. Regul Pept 120: 5–13, 2004 - PubMed
    1. Baker KM, Kumar R. Intracellular angiotensin II induces cell proliferation independent of AT1 receptor. Am J Physiol Cell Physiol 291: C995–C1001, 2006 - PubMed
    1. Boccara F, Cohen A. Interplay of diabetes and coronary heart disease on cardiovascular mortality. Heart 90: 1371–1373, 2004 - PMC - PubMed

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