What is the clinical evidence from this study?

Study design: Other. Population: Mitochondrial function and aging. Intervention: AT2R agonist (CGP421140) and AT1R blocker (losartan) vs. Baseline/Control or untreated. Primary outcome: Mitochondrial NO production (fluorescence arbitrary units) (p=<0.001).

August 18, 2011

Identification and characterization of a functional mitochondrial angiotensin system

Q: What are the key findings of this study?

Activation of mitochondrial angiotensin II type 2 receptors stimulates nitric oxide production and modulates respiration, while age-related declines in these receptors are reversed by losartan.

Key Result

Activation of mitochondrial angiotensin II type 2 receptors stimulates nitric oxide production and modulates respiration, while age-related declines in these receptors are reversed by losartan.

Structured PICO

Population

Basic science study utilizing human cells, isolated mitochondria, and mouse/rat models to identify and characterize a functional mitochondrial angiotensin system.

Intervention

AT2R agonist (CGP421140), AT2R antagonist (PD-123319), and AT1R blocker (losartan 40-60 mg/kg/day for 20 weeks)

Comparator

Untreated controls, young vs. aged mice

Outcome

Subcellular localization of AT1R and AT2R, mitochondrial NO production, and mitochondrial respirationsurrogate

This study provides the first evidence of a functional mitochondrial angiotensin system that regulates nitric oxide production and respiration, revealing a novel subcellular target for RAS modulators.

Main Result

Absolute Event Rate: 0.6% vs 0.52%

p-value: p=<0.001

Limitations

Whether AT2R-coupled NO is produced on the matrix side of the inner membrane remains to be determined.
The role that active metabolites of Ang II (like Ang III) play in the activation of the MAS requires further study.
Further studies are needed to determine the role of the MAS in the production of reactive oxygen species.

Abstract

The renin-angiotensin (Ang) system regulates multiple physiological functions through Ang II type 1 and type 2 receptors. Prior studies suggest an intracellular pool of Ang II that may be released in an autocrine manner upon stretch to activate surface membrane Ang receptors. Alternatively, an intracellular renin-Ang system has been proposed, with a primary focus on nuclear Ang receptors. A mitochondrial Ang system has not been previously described. Here we report that functional Ang II type 2 receptors are present on mitochondrial inner membranes and are colocalized with endogenous Ang. We demonstrate that activation of the mitochondrial Ang system is coupled to mitochondrial nitric oxide production and can modulate respiration. In addition, we present evidence of age-related changes in mitochondrial Ang receptor expression, i.e., increased mitochondrial Ang II type 1 receptor and decreased type 2 receptor density that is reversed by chronic treatment with the Ang II type 1 receptor blocker losartan. The presence of a functional Ang system in human mitochondria provides a foundation for understanding the interaction between mitochondria and chronic disease states and reveals potential therapeutic targets for optimizing mitochondrial function and decreasing chronic disease burden with aging.

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