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Angiotensin‐converting enzyme 2: a new target for neurogenic hypertension

Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
Experimental physiology (Impact Factor: 2.87). 04/2010; 95(5):601 - 606. DOI: 10.1113/expphysiol.2009.047407

ABSTRACT Overactivity of the renin–angiotensin system (RAS) is involved in the pathogenesis of hypertension, and an overactive brain RAS has been highlighted in several genetic and experimental models. Until now, angiotensin II (Ang II) was thought to be the main effector of this system, and the angiotensin-converting enzyme (ACE)–Ang II–Ang II type 1 receptor axis was the main target for antihypertensive therapies. A new member of the RAS, ACE2 (angiotensin-converting enzyme type 2), has been identified in organs and tissues related to cardiovascular function (e.g. heart, kidney and blood vessels) and appears to be part of a counter-regulatory pathway to buffer the excess of Ang II. We recently identified the ACE2 protein in brain regions involved in the central regulation of blood pressure and showed that it regulates, and is regulated by, other components of the RAS. Here, we present evidence for the involvement of brain ACE2 in the central regulation of blood pressure, autonomic and cardiac function. We show that lack of ACE2 is deleterious for the central regulation of blood pressure and that brain ACE2 gene therapy can restore baroreflex and autonomic functions and prevent the development of hypertension. Additionally, and independently of a reduction in Ang II levels, we will highlight some of the mechanisms responsible for the beneficial effects of central ACE2 in cardiovascular function.

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Available from: Yumei Feng, Jan 05, 2015
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    • "The RAS plays a fundamental role in the regulation of BP and kidney and heart development. It is now well established that ACE2 adjusts AT2R and angiotensin (1–7) Mas as an endogenous counter-regulatory pathway within the RAS, opposing the development of hypertension [26]. Our data demonstrated that neonatal DEX-induced programmed hypertension, which is associated with decreased ACE2 expression in the kidney and heart. "
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    ABSTRACT: Adulthood hypertension can be programmed by corticosteroid exposure in early life. Oxidative stress, epigenetic regulation by histone deacetylases (HDACs), and alterations of renin-angiotensin system (RAS) are involved in the developmental programming of hypertension. We examined whether melatonin prevented neonatal dexamethasone (DEX)-induced programmed hypertension and how melatonin prevented these processes. We also examined whether HDAC inhibition by trichostatin A (TSA, a HDAC inhibitor) had similar effects. Male offspring were assigned to 5 groups (n=6/group): control, DEX, melatonin, DEX+melatonin, and DEX+TSA. Male rat pups were injected i.p. with DEX on day 1 (0.5mg/kg BW), day 2 (0.3mg/kg BW), and day 3 (0.1mg/kg BW) after birth. Melatonin was administered in drinking water at the dose of 0.01% during the lactation period. The DEX+TSA group received DEX and 0.5mg/kg TSA subcutaneous injection once daily for 1 week. All rats were killed at 16 weeks of age. Neonatal DEX exposure induced hypertension in male offspring at 16 weeks of age, which melatonin prevented. Neonatal DEX exposure decreased gene expression related to apoptosis, nephrogenesis, RAS, and sodium transporters. Yet DEX treatment increased protein levels of HDAC-1, -2, and -3 in the kidney. Melatonin therapy preserved the decreases of gene expression and decreased HDACs. Similarly, HDAC inhibition prevented DEX-induced programmed hypertension. In conclusion, melatonin therapy exerts a long-term protection against neonatal DEX-induced programmed hypertension. Its beneficial effects include alterations of RAS components and inhibition of class I HDACs. Given that the similar protective effects of melatonin and TSA, melatonin might inhibit HDACs to epigenetic regulation of hypertension-related genes to prevent programmed hypertension.
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    • "It is described that ACE2 counteracts angiotensin II effects by decreasing the expression of angiotensin type 1 receptors and increases production of angiotensin (1–7), which is vasoprotective; the latter also increases production of nitric oxide, triggering alterations in blood flow and presumably neuronal integration. Feng et al. (2010) show that blocking ACE2 activity in the brain causes disruption to normal cardiovascular control, yet its activity appears suppressed in conditions of hypertension, since overexpression lowers blood pressure in a hypertensive animal model; the latter has obvious clinical relevance. All told, this series of papers provides the reader with up-to-date viewpoints on the current major issues concerning hypertension, some novel therapeutic approaches being trialed presently, the latest in potential central nervous mechanisms driving up blood pressure and some possible new therapeutic strategies to exploit in the future. "
    Experimental physiology 05/2010; 95(5):569-71. DOI:10.1113/expphysiol.2009.047282 · 2.87 Impact Factor
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