Small proline-rich protein 1A is a gp130 pathway- and stress-inducible cardioprotective protein

Abstract

The interleukin-6 cytokines, acting via gp130 receptor pathways, play a pivotal role in the reduction of cardiac injury induced by mechanical stress or ischemia and in promoting subsequent adaptive remodeling of the heart. We have now identified the small proline-rich repeat proteins (SPRR) 1A and 2A as downstream targets of gp130 signaling that are strongly induced in cardiomyocytes responding to biomechanical/ischemic stress. Upregulation of SPRR1A and 2A was markedly reduced in the gp130 cardiomyocyte-restricted knockout mice. In cardiomyocytes, MEK1/2 inhibitors prevented SPRR1A upregulation by gp130 cytokines. Furthermore, binding of NF-IL6 (C/EBPb) and c-Jun to the SPRR1A promoter was observed after CT-1 stimulation. Histological analysis revealed that SPRR1A induction after mechanical stress of pressure overload was restricted to myocytes surrounding piecemeal necrotic lesions. A similar expression pattern was found in postinfarcted rat hearts. Both in vitro and in vivo ectopic overexpression of SPRR1A protected cardiomyocytes against ischemic injury. Thus, this study identifies SPRR1A as a novel stress-inducible downstream mediator of gp130 cytokines in cardiomyocytes and documents its cardioprotective effect against ischemic stress.

Gene expression pattern and hormonal regulation of Small Proline-Rich Protein 2 family members in the female mouse reproductive system during the estrous cycle and pregnancy

“…In the biliary tract, the expression of SPRR2 members is highly induced under stress injury [29]. Similarly, SPRR1A and SPRR2A are strongly induced in cardiomyocytes responding to biomechanical/ischemic stress, and these proteins could protect cardiomyocytes against ischemic injury [30]. The SPRR2A protein was also reported to be highly induced in gastric mucosa upon Helicobacter pylori infection in the human stomach [31].…”

Upregulation of SPRR3 Promotes Colorectal Tumorigenesis

“…SW480/ SPRR3 cells showed a high anchorageindependent proliferation rate, supporting the hypothesis that increased SPRR3 plays a role in colorectal tumorigenesis. It has been reported that SPRR1A protein is upregulated in, and is protective against, hypoxia-induced stress (10). To further elucidate the mechanisms of molecular control of SPRR3 in colorectal cancer, we next examined the effect of SPRR3 on AKT signaling.…”

“…SPRR proteins are known to be markers for terminal squamous cell differentiation, but they also function in nonsquamous tissues (9). For example, SPRR1A is induced by and is protective against ischemic stress in cardiomyocytes (10). It has recently been reported that SPRR3 is upregulated in celiac disease and also by prolonged exposure to cyclic strain (11,12).…”

Small proline-rich proteins (SPRR) function as SH3 domain ligands, increase resistance to injury and are associated with epithelial–mesenchymal transition (EMT) in cholangiocytes

“…Pradervand (50) Biomechanical/ischemic stress and remodeling (heart) SPRR1A, SPRR2A 2-35-fold induction 4 days after pressure over load or after one week in myocytes near infarcts; myocytes with transduced expression showed resistance to ischemic injury (mice) Gotter (51) Cultured (thymic epithelium) SPRR1B SPRR upregulated in cultured thymic epithelium; likely related to squamous differentiation (human) Bonilla (52) Nerve injury, axonal outgrowth, remodeling, repair (peripheral nerves) SPRR1A > 60-fold induction in injured peripheral neurons; associated with axonal outgrowth (mice) Fischer (53) Injury, growth, and remodeling in (central neurons)…”