Blockage of Angiotensin II type 2 receptor prevents thyroxine-mediated cardiac hypertrophy by blocking Akt activation

The role of the angiotensin II type 2 receptor (AT2R) in cardiovascular physiology remains elusive. We have developed an in vivo lentiviral vector-mediated gene transfer system to study the physiological functions of the AT2R. Our objectives in this study were to determine whether the AT2R influences cardiac hypertrophy and myocardial and perivascular fibrosis in a nongenetic rat model of hypertension. Lentiviral vector containing the AT2R or saline was injected intracardially in 5-day-old Sprague-Dawley rats. This resulted in a persistent overexpression of the AT2R in cardiac tissues. At 15 wk of age, animals were infused with either 200 ng·kg−1·min−1 of angiotensin II or saline by implantation of a 4-wk osmotic minipump. This resulted in an increase in blood pressure (BP) that reached maximal by 2 wk of treatment and was associated with a 123% increase in left ventricular wall thickness (LVWT) and a 129% increase in heart weight to body weight ratios (HW/BW). In addition, the increase in cardiac hypertrophy was associated with a 300% and 158% increase in myocardial and perivascular fibrosis, respectively. Cardiac transduction of the AT2R resulted in an 85% attenuation of LVWT, 91% attenuation of HW/BW, and a 43% decrease in myocardial fibrosis induced by angiotensin infusion. These improvements in cardiac pathology were observed in the absence of attenuation of high BP. Thus our observations indicate that long-term expression of the AT2R in the heart attenuates cardiac hypertrophy and fibrosis in a nongenetic rat model of hypertension.

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Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy

Physiological Genomics ◽

10.1152/physiolgenomics.00029.2005 ◽

2006 ◽

Vol 26 (3) ◽

pp. 180-191 ◽

Cited By ~ 106

Author(s):

Shawn D. Hingtgen ◽

Xin Tian ◽

Jusan Yang ◽

Shannon M. Dunlay ◽

Andrew S. Peek ◽

...

Keyword(s):

Angiotensin Ii ◽

Nadph Oxidase ◽

Cardiac Hypertrophy ◽

Dominant Negative ◽

Time Dependent ◽

Neonatal Rat ◽

Signaling Cascade ◽

Cardiomyocyte Hypertrophy ◽

Ang Ii ◽

Akt Activation

Angiotensin II (ANG II) has profound effects on the development and progression of pathological cardiac hypertrophy; however, the intracellular signaling mechanisms are not fully understood. In this study, we used genetic tools to test the hypothesis that increased formation of superoxide (O2−·) radicals from a Rac1-regulated Nox2-containing NADPH oxidase is a key upstream mediator of ANG II-induced activation of serine-threonine kinase Akt, and that this signaling cascade plays a crucial role in ANG II-dependent cardiomyocyte hypertrophy. ANG II caused a significant time-dependent increase in Rac1 activation and O2−· production in primary neonatal rat cardiomyocytes, and these responses were abolished by adenoviral (Ad)-mediated expression of a dominant-negative Rac1 (AdN17Rac1) or cytoplasmic Cu/ZnSOD (AdCu/ZnSOD). Moreover, both AdN17Rac1 and AdCu/ZnSOD significantly attenuated ANG II-stimulated increases in cardiomyocyte size. Quantitative real-time PCR analysis demonstrated that Nox2 is the homolog expressed at highest levels in primary neonatal cardiomyocytes, and small interference RNA (siRNA) directed against it selectively decreased Nox2 expression by >95% and abolished both ANG II-induced O2−· generation and cardiomyocyte hypertrophy. Finally, ANG II caused a time-dependent increase in Akt activity via activation of AT1 receptors, and this response was abolished by Ad-mediated expression of cytosolic human O2−· dismutase (AdCu/ZnSOD). Furthermore, pretreatment of cardiomyocytes with dominant-negative Akt (AdDNAkt) abolished ANG II-induced cellular hypertrophy. These findings suggest that O2−· generated by a Nox2-containing NADPH oxidase is a central mediator of ANG II-induced Akt activation and cardiomyocyte hypertrophy, and that dysregulation of this signaling cascade may play an important role in cardiac hypertrophy.

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Angiotensin II Type 2 Receptors and Cardiac Hypertrophy in Women With Hypertrophic Cardiomyopathy

Hypertension ◽

10.1161/hy1101.096114 ◽

2001 ◽

Vol 38 (6) ◽

pp. 1278-1281 ◽

Cited By ~ 37

Author(s):

Jaap Deinum ◽

Jeanette M.G. van Gool ◽

Marcel J.M. Kofflard ◽

Folkert J. ten Cate ◽

A.H. Jan Danser

Keyword(s):

Angiotensin Ii ◽

Hypertrophic Cardiomyopathy ◽

Cardiac Hypertrophy

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Thyroid Hormone Increases TGF-β1 in Cardiomyocytes Cultures Independently of Angiotensin II Type 1 and Type 2 Receptors

International Journal of Endocrinology ◽

10.1155/2010/384890 ◽

2010 ◽

Vol 2010 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Gabriela Placoná Diniz ◽

Marcela Sorelli Carneiro-Ramos ◽

Maria Luiza Morais Barreto-Chaves

Keyword(s):

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Transforming Growth Factor ◽

Cardiac Fibroblasts ◽

Angiotensin Ii Receptors ◽

Cardiomyocyte Hypertrophy ◽

Tgf Β1

TH-induced cardiac hypertrophyin vivois accompanied by increased cardiac Transforming Growth Factor-β1 (TGF-β1) levels, which is mediated by Angiotensin II type 1 receptors (AT1R) and type 2 receptors (AT2R). However, the possible involvement of this factor in TH-induced cardiac hypertrophy is unknown. In this study we evaluated whether TH is able to modulate TGF-β1 in isolated cardiac, as well as the possible contribution of AT1R and AT2R in this response. The cardiac fibroblasts treated withT3did not show alteration on TGF-β1 expression. However, cardiomyocytes treated withT3presented an increase in TGF-β1 expression, as well as an increase in protein synthesis. The AT1R blockade prevented theT3-induced cardiomyocyte hypertrophy, while the AT2R blockage attenuated this response. TheT3-induced increase on TGF-β1 expression in cardiomyocytes was not changed by the use of AT1R and AT2R blockers. These results indicate that Angiotensin II receptors are not implicated inT3-induced increase on TGF-βexpression and suggest that the trophic effects exerted byT3on cardiomyocytes are not dependent on the higher TGF-β1 levels, since the AT1R and AT2R blockers were able to attenuate theT3-induced cardiomyocyte hypertrophy but were not able to attenuate the increase on TGF-β1 levels promoted byT3.

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