p66Shc has classically been implicated in cellular responses to oxidative stress and redox-sensitive processes associated with aging and longevity. In addition to growth factors, which typically activate p66Shc, recent evidence indicates that steroid hormones stimulate phosphorylation of the protein. Moreover, aldosterone also induces activation of p66Shc in both isolated vascular smooth muscle cells and in vascular tissue from mice infused with aldosterone. Interestingly, this effect is blunted in aldosterone-infused mice deficient in Nox1. Thus aldosterone may regulate p66Shc through Nox1-senstive mechanisms. However, the (patho)physiological significance of aldosterone-Nox1-p66Shc signaling in the cardiovascular system is unclear, but may play a role in pro-fibrotic processes, especially since aldosterone and reactive oxygen species are important players in cardiovascular fibrosis.
Aldosterone through the mineralocorticoid receptor, induces activation of p66Shc which stimulates pro-fibrotic signaling pathways that promote cardiac, renal and vascular fibrosis. These phenomena are amplified in aldosterone-dependent hypertension.To our knowledge, nothing is known about aldosterone, p66Shc and cardiovascular fibrosis.
The overall objective of this in vivo study is to demonstrate that in aldosterone-infused mice, activation of p66Shc is associated with cardiovascular and renal fibrosis and that these phenomena are mediated through mineralocorticoid receptors. We will study p66Shc-deficient mice, where aldosterone-induced fibrosis could be prevented or ameliorated. These phenomena may be independent of changes in blood pressure.
Expected results
Findings from our study will demonstrate that aldosterone induces hypertension, which is associated with cardiovascular and renal fibrosis and increased phosphorylation of p66Shc and activation of pro-fibrotic/pro-inflammatory pathways. These events may occur independently of ROS.
Spironolactone will inhibit aldosterone actions, indicating the importance of mineralocorticoid activation.
In p66Shc mice, aldosterone/MR activation will be downregulated, with associated decrease in fibrosis. These events may be independent of blood pressure lowering.
Significance.
Our in vivo study will advance the field of aldosterone biology and will identify a new downstream pro-fibrotic signaling pathway through p66Shc.
Moreover, we will define fibrosis as a new biological response of p66Shc.
Considering the growing interest in p66Shc inhibitors as a therapeutic strategy our findings may suggest a novel approach in treating cardiovascular-renal fibrosis in conditions associated with hyperaldosteronism.