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1 Molecular Cardiology, Texas A&M Health Science Center, Temple, Texas, United States
2 Internal Medicine, Scott & White, Temple, Texas, United States
3 Investigative pathology, Scott & White, Temple, Texas, United States
* To whom correspondence should be addressed. E-mail: kumar{at}medicine.tamhsc.edu.
The prevailing paradigm is that cardiac angiotensin II (Ang II) is synthesized in the extracellular space, from components of the circulating and/or local renin angiotensin system. The recent discovery of intracrine effects of Ang II, led us to determine whether Ang II synthesis occurs intracellularly in neonatal rat ventricular myocytes (NRVM). NRVM, incubated in serum-free medium, were exposed to isoproterenol or high glucose, in the absence or presence of candesartan, the latter to prevent AT1-mediated internalization of Ang II. Ang II was measured in cell lysates and the culture medium, which represented intra- and extracellularly synthesized Ang II, respectively. Isoproterenol increased the Ang II concentration in both cell lysates and medium of NRVM, in the absence or presence of candesartan. High glucose markedly increased Ang II synthesis; however, this was observed only in the cell lysates, both in the absence and presence of candesartan. Western analysis showed increased intracellular levels of angiotensinogen, renin and chymase, in high glucose exposed cells. Confocal immunofluorocytometry confirmed Ang II in the cytoplasm and nucleus of high glucose exposed NRVM and along the actin filaments in isoproterenol exposed cells. Ang II synthesis was dependent on renin and chymase under high glucose and renin and ACE in isoproterenol exposed cells. In summary, the site of Ang II synthesis, localization, and the synthetic pathway in NRVM, is stimulus dependent. Significantly, NRVM synthesized and retained Ang II intracellularly, which redistributed to the nucleus under high glucose conditions, suggesting a role for an intracrine mechanism in diabetic conditions.
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