The α and Δ Isoforms of CREB1 Are Required to Maintain Normal Pulmonary Vascular Resistance

Abstract

Chronic hypoxia causes pulmonary hypertension associated with structural alterations in pulmonary vessels and sustained vasoconstriction. The transcriptional mechanisms responsible for these distinctive changes are unclear. We have previously reported that CREB1 is activated in the lung in response to alveolar hypoxia but not in other organs. To directly investigate the role of α and Δ isoforms of CREB1 in the regulation of pulmonary vascular resistance we examined the responses of mice in which these isoforms of CREB1 had been inactivated by gene mutation, leaving only the β isoform intact (CREBαΔ mice). Here we report that expression of CREB regulated genes was altered in the lungs of CREBαΔ mice. CREBαΔ mice had greater pulmonary vascular resistance than wild types, both basally in normoxia and following exposure to hypoxic conditions for three weeks. There was no difference in rho kinase mediated vasoconstriction between CREBαΔ and wild type mice. Stereological analysis of pulmonary vascular structure showed characteristic wall thickening and lumen reduction in hypoxic wild-type mice, with similar changes observed in CREBαΔ. CREBαΔ mice had larger lungs with reduced epithelial surface density suggesting increased pulmonary compliance. These findings show that α and Δ isoforms of CREB1 regulate homeostatic gene expression in the lung and that normal activity of these isoforms is essential to maintain low pulmonary vascular resistance in both normoxic and hypoxic conditions and to maintain the normal alveolar structure. Interventions that enhance the actions of α and Δ isoforms of CREB1 warrant further investigation in hypoxic lung diseases.

Transcription factor cAMP response element modulator (Crem) restrains Pdgf-dependent proliferation of vascular smooth muscle cells in mice

“…Previous findings by catheterization of the left ventricle showed that Crem −/− mice exhibit a lower left-ventricular blood pressure than Crem +/+ animals [ 27 ], which could be associated with alterations in the contractility of the vascular system. Moreover, a loss of the Creb isoforms α and Δ was linked to a higher pulmonary vascular resistance [ 23 ]. Our analysis revealed that neither the PE- or prostaglandin-mediated vasoconstriction nor the β-adrenergic, muscarinic, or NO-dependent vasorelaxation was different concerning the maximal effects or the EC 50 /IC 50 in Crem −/− mice versus Crem +/+ mice.…”

“…Cyclic AMP promotes quiescence and maintenance in vascular smooth muscle cells (VSMCs) and the β-adrenoceptor, and cAMP-dependent activation of PKA is important to sustain their contractile function under normal conditions [ 35 ]. Creb is an important downstream target of PKA, and changes in Creb phosphorylation or function are correlated with the regulation of cell proliferation [ 18 , 41 ], apoptosis [ 42 ], migration [ 15 , 29 ], VSMC hypertrophy [ 8 ], or vascular resistance [ 23 ]. Elevated cAMP levels inhibit platelet-derived growth factor (Pdgf)-stimulated VSMC growth by PKA/Creb-dependent induction of transformation-related protein 53 (p53) and cyclin-dependent kinase inhibitor 1A (p21) and by inhibition of mitogen-activated protein kinase (MAPK) signaling [ 2 , 11 ].…”

The effects of genetic deletion of Macrophage migration inhibitory factor on the chronically hypoxic pulmonary circulation

“…The hearts were separated from the lungs, fixed by immersion in paraformaldehyde (4% w/v in normal saline) and used to determine the ratio of the right ventricle to the left ventricle plus septum (RV/LV + S) as previously described. 29 Briefly, the atria were removed at the level of the atrioventricular junction in the plane of the mitral and tricuspid annuli (i.e. at the level of the openings of the tricuspid and mitral valves where the valve leaflets attach).…”

The potential role of TRPV1 in pulmonary hypertension: Angel or demon?

“…In contrast, there are reports showing the downregulation of pCREB in PAH PASMCs and the protective role of CREB from proliferation and remolding by regulating phosphatase and tension homolog (PTEN), a tumor suppressor gene, and mitochondrial calcium uniporter (MCU), a mitochondrial calcium uptake protein that can decrease [Ca 2+ ] i [36,37]. These contradictory results may be due to the presence of three types of isoforms of CREB, which may produce different effects [38].…”