Retinoic Acid Signalling Is Activated in the Postischemic Heart and May Influence Remodelling

Abstract

BackgroundAll-trans retinoic acid (atRA), an active derivative of vitamin A, regulates cell differentiation, proliferation and cardiac morphogenesis via transcriptional activation of retinoic acid receptors (RARs) acting on retinoic acid response elements (RARE).We hypothesized that the retinoic acid (RA) signalling pathway is activated in myocardial ischemia and postischemic remodelling.Methods and FindingsMyocardial infarction was induced through ligating the left coronary artery in mice. In vivo cardiac activation of the RARs was measured by imaging RARE-luciferase reporter mice, and analysing expression of RAR target genes and proteins by real time RT-PCR and western blot. Endogenous retinoids in postinfarcted hearts were analysed by triple-stage liquid chromatography/tandem mass spectrometry. Cardiomyocytes (CM) and cardiofibroblasts (CF) were isolated from infarcted and sham operated RARE luciferase reporter hearts and monitored for RAR activity and expression of target genes. The effect of atRA on CF proliferation was evaluated by EdU incorporation. Myocardial infarction increased thoracic RAR activity in vivo (p<0.001), which was ascribed to the heart through ex vivo imaging (p = 0.002) with the largest signal 1 week postinfarct. This was accompanied by increased cardiac gene and protein expression of the RAR target genes retinol binding protein 1 (p = 0.01 for RNA, p = 0,006 for protein) and aldehyde dehydrogenase 1A2 (p = 0.04 for RNA, p = 0,014 for protein), while gene expression of cytochrome P450 26B1 was downregulated (p = 0.007). Concomitantly, retinol accumulated in the infarcted zone (p = 0.02). CM and CF isolated from infarcted hearts had higher luminescence than those from sham operated hearts (p = 0.02 and p = 0.008). AtRA inhibited CF proliferation in vitro (p = 0.02).ConclusionThe RA signalling pathway is activated in postischemic hearts and may play a role in regulation of damage and repair during remodelling.

Cardiac dysfunction in β-carotene-15,15′-dioxygenase-deficient mice is associated with altered retinoid and lipid metabolism

“…ATRA signaling has been reported by Bilbija et al (5) to be activated in the mouse heart after permanent coronary artery ligation. These investigators further proposed that ATRA signaling may play a role in regulating damage and repair during heart remodeling (5).…”

Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification

“…Furthermore, the effect of PX-478 is limited to hypoxia, as angiogenic signaling is not altered in the presence of PX-478 under normoxic conditions (28). PX-478 does not appear to alter retinoic acid signaling, a pathway previously shown to affect HO formation (32). Separately, we used rapamycin, which inhibits Hif1α through the mammalian target of rapamycin (mTOR) (16,33).…”

Retinoic acid and sodium butyrate suppress the cardiac expression of hypertrophic markers and proinflammatory mediators in Npr1 gene-disrupted haplotype mice

“…The treatments with RA or SB, alone or in combination prevented the expression of MMPs and activated the expression of TIMPs in heart tissue of Npr1 ϩ/Ϫ mice. Moreover, in vivo studies have shown that RA not only prevents ventricular fibrosis and remodeling during the development of hypertension but also activates RA signaling after myocardial infarction (4,37). Those previous findings support our hypothesis regarding the protective mechanisms of RA and SB in 1-copy haplotype Npr1 mice.…”