Blood pressure homeostasis is maintained by a P311–TGF-β axis

Abstract

P311 is an 8-kDa intracellular protein that is highly conserved across species and is expressed in the nervous system as well as in vascular and visceral smooth muscle cells. P311-null (P311 -/-) mice display learning and memory defects, but alterations in their vasculature have not been previously described. Here we report that P311 -/-mice are markedly hypotensive with accompanying defects in vascular tone and VSMC contractility. Functional abnormalities in P311 -/-mice resulted from decreased total and active levels of TGF-β1, TGF-β2, and TGF-β3 that arise as a specific consequence of decreased translation. Vascular hypofunctionality was fully rescued in vitro and in vivo by exogenous TGF-β1-TGF-β3. Conversely, P311-transgenic (P311 TG ) mice had elevated levels of TGF-β1-TGF-β3 and subsequent hypertension. Consistent with findings attained in mouse models, arteries recovered from hypertensive human patients displayed increased P311 expression. Thus, we identified P311 as the first protein known to modulate TGF-β translation and the first pan-regulator of TGF-β expression under steady-state conditions. Together, our findings point to P311 as a critical blood pressure regulator and establish a potential link between P311 expression and the development of hypertensive disease.

Neuronal Protein 3.1 Deficiency Leads to Reduced Cutaneous Scar Collagen Deposition and Tensile Strength due to Impaired Transforming Growth Factor-β1 to -β3 Translation

“…2 Although the molecular mechanism of P311 action remained unknown for years, we recently found that P311 is an RNA-binding protein that stimulates TGF-b1 to -b3 translation in vivo in the vascular smooth muscle as well as in vascular smooth muscle and NIH-3T3 cells in vitro. 1,2 Because TGF-b plays critical roles in fibrogenesis, 39 here we conducted studies to determine whether P311 may have a function in cutaneous scar formation. We found that P311 expression is up-regulated in excisional wounds compared with normal skin during the proliferative phase of healing, and it is further increased in expression during the remodeling phase, when the scar is formed.…”

“…Immunohistochemistry (IHC) was performed at the University of Chicago Pathology Core Facility. Briefly, The IHC procedure was applied to formalin-fixed, paraffin-embedded 5-mm tissue sections, which were incubated with anti-human P311 antibody 2 (1:50 dilution) after antigen unmasking by boiling in fresh citrate buffer. The reactions were developed with Vectastain ABC kit (Vector Laboratories, Burlingame, CA).…”

“…Immunoblots were performed as previously described. 2 The following antibodies were used: anti-P311, 2 anti-pSMAD2, and anti-SMAD2 (both from Cell Signaling Technology, Danvers, MA), antipSMAD3 and anti-SMAD3 (both from R&D Systems. ), anti-COL1A1 and anti-COL3A1 (both from Abcam, Cambridge, MA).…”

“…10,11 More recently, however, we reported that genetic ablation of P311 leads to decreased vascular smooth muscle cell contractility, hypotonic blood vessels, and vascular hypotension due to a defect in transforming growth factor (TGF)-b1 to -b3 translation. 2 Basic Local Alignment Search Tool (BLAST) searching reveals that P311 does not belong to any known protein family and has no established functional motif that might indicate function. Therefore, the molecular mechanisms of P311 biological action have remained unknown for years, until recently when we found that P311 is an intrinsically disordered protein requiring, therefore, an interacting partner to acquire tertiary structure and function.…”

Proprotein convertase furin/PCSK3 and atherosclerosis: New insights and potential therapeutic targets

“…Evidence suggests that TGF-b signaling pathway is also involved in BP homeostasis [56]. When initially synthesized, TGF-b1 is an inactive precursor polypeptide.…”