All‐trans retinoic acid prevents angiotensin II‐ and mechanical stretch‐induced reactive oxygen species generation and cardiomyocyte apoptosis

Abstract

Cardiomyocyte apoptosis has an important role in the transition from compensatory cardiac remodeling to heart failure. All-trans retinoic acid (RA), a bioactive vitamin A derivative, prevents stretch- and angiotensin II (Ang II)-induced cardiac hypertrophy. However, the anti-apoptotic potential of RA in the heart remains unexplored. Here, we demonstrate that stretch- and Ang II-induced apoptosis is prevented by RA in neonatal cardiomyocytes. RA improved mitochondrial function by inhibiting the stretch- and Ang II-induced reduction in mitochondrial membrane potential, cytochrome c release and by increasing the Bcl2/Bax ratio. RA inhibited stretch- and Ang II-induced intracellular reactive oxygen species (ROS) generation and upregulated the SOD2 level. Hydrogen peroxide-induced increases in the number of TUNEL-positive cells and percentage of Annexin V positive cells, were dose-dependently inhibited by RA. The thiol antioxidant, N-acetyl cysteine (NAC), completely inhibited stretch- and Ang II-induced apoptosis. Using diazoxide (mitochondrial ATP-sensitive K(+) channel opener) and SDS (NADPH oxidase activator), we confirmed that RA suppressed both mitochondrial- and NADPH oxidase-derived ROS. We also observed that both RAR and RXR were involved in preventing Ang II- and stretch-induced ROS production and apoptosis, by using selective retinoid receptor agonists and antagonists. Our data provide the first evidence that RA prevents Ang II and stretch induced apoptosis, by inhibiting ROS generation and increasing the anti-oxidant defense system, suggesting that RA-mediated signaling may provide a new therapeutic target for the prevention of the cardiac remodeling process.

13-cis-Retinoic acid specific down-regulation of angiotensin type 1 receptor in rat liver epithelial and aortic smooth muscle cells

“…The atRA treatment has been shown to up-regulate superoxide dismutase (Choudhary et al 2008a). This was strongly supported from a previous observation that atRA treatment prevented AngII-induced oxidative stress in cardiomyocytes (Choudhary et al 2008b). Therefore, the conclusion was that reduction of the oxidative stress by retinoic acid nullified the AngII-mediated cellular damage and inhibited cellular apoptosis.…”

Association of all-trans retinoic acid treatment with the renin-angiotensin aldosterone system expression in glomerulosclerosis rats

“…They also first reported the evidence that ATRA prevented angiotensin IIand stretched-induced apoptosis. 27 He et al 28 found that ATRA inhibited the angiotensin II-induced increase in cell growth and collagen secretion in neonatal rats with cardiac fibroblasts. Haxsen et al 29 reported that ATRA could inhibit the actions of angiotensin II on vascular smooth muscle cells.…”

Glutathione peroxidase 3, a new retinoid target gene, is crucial for human skeletal muscle precursor cell survival

“…RA also plays a role in maintaining the integrity of hematopoietic cells (Oritani et al, 1992) and retinal precursors (Kholodenko et al, 2007). RA may prevent cardiac remodeling and ventricular hypertrophy by inhibiting the production of angiotensin II and ROS formation and by increasing antioxidant defenses (Choudhary et al, 2008). Different anti-apoptotic genes have been identified as retinoid responsive, such as SOD-2 in neuroblastoma and acute myeloblastic leukemia cells (Kiningham et al, 2008), B-cl2 in leukemic cells (Yin et al, 2005), Trx in airway epithelial cells (Chang et al, 2002) and GPx-2 in human breast cancer cells (Chu et al, 1999).…”