Natriuretic peptide receptor a promotes gastric malignancy through angiogenesis process

Gastric cancer (GC) ranks the third among global cancer-related mortality, especially in East Asia. Angiogenesis plays an important role in promoting tumor progression, and clinical trials have demonstrated that anti-angiogenesis therapy is effective in GC management. Natriuretic peptide receptor A (NPRA) functions significantly in promoting GC development and progression. Whether NPRA can promote angiogenesis of GC remains unclear. Tumor samples collection and immunohistochemical experiment showed that the expression of NPRA was positively correlated with the expression of CD31 and vessel density. In vivo and in vitro analysis showed that NPRA could promote GC-associated angiogenesis and tumor metastasis. Results of Co-IP/MS showed that NPRA could prevent HIF-1α from being degraded by binding to HIF-1α. Protection of HIF-1α improved VEGF levels and thus promoted angiogenesis. In summary, NPRA protected HIF-1α from proteolysis by binding to HIF-1α, increased the expression of HIF-1α, and promoted GC angiogenesis. This study has discovered a new mechanism for NPRA to promote gastric cancer development and a new regulatory mechanism for HIF-1α.

Molecular Signaling Mechanisms and Function of Natriuretic Peptide Receptor-A in the Pathophysiology of Cardiovascular Homeostasis

The discovery of atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP) and their cognate receptors has greatly increased our knowledge of the control of hypertension and cardiovascular homeostasis. ANP and BNP are potent endogenous hypotensive hormones that elicit natriuretic, diuretic, vasorelaxant, antihypertrophic, antiproliferative, and antiinflammatory effects, largely directed toward the reduction of blood pressure (BP) and cardiovascular diseases (CVDs). The principal receptor involved in the regulatory actions of ANP and BNP is guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), which produces the intracellular second messenger cGMP. Cellular, biochemical, molecular, genetic, and clinical studies have facilitated understanding of the functional roles of natriuretic peptides (NPs), as well as the functions of their receptors, and signaling mechanisms in CVDs. Transgenic and gene-targeting (gene-knockout and gene-duplication) strategies have produced genetically altered novel mouse models and have advanced our knowledge of the importance of NPs and their receptors at physiological and pathophysiological levels in both normal and disease states. The current review describes the past and recent research on the cellular, molecular, genetic mechanisms and functional roles of the ANP-BNP/NPRA system in the physiology and pathophysiology of cardiovascular homeostasis as well as clinical and diagnostic markers of cardiac disorders and heart failure. However, the therapeutic potentials of NPs and their receptors for the diagnosis and treatment of cardiovascular diseases, including hypertension, heart failure, and stroke have just begun to be expanded. More in-depth investigations are needed in this field to extend the therapeutic use of NPs and their receptors to treat and prevent CVDs.

Abstract P230: Depletion Of Cyclic-gmp Levels And The Inhibition Of Cgks Activate P21 Cip1 /p27 Kip1 Pathways And Trigger High Blood Pressure With Renal Fibrosis And Dysfunction

Targeted-deletion of Npr1 gene (coding for guanylyl cyclase/natriuretic peptide receptor-A, GC-A/NPRA) exhibits hypertrophic and proliferative effects in target organs of Npr 1 gene-knockout mice. Fibrosis and hypertrophy are regulated by p21 Cip1 and p27 Kip1 , cell-cycle regulatory proteins that inhibit target cyclin and cyclin-dependent kinase (cyclin-CDK) complex. We examined the activation of CDK blocker (p21 Cip1 /p27 Kip1 ) in Npr1 gene-knockout (0-copy; Npr 1 -/- ) mice and guanylyl cyclase (GC) inhibitor, A71915-treated and cGMP-dependent protein kinase (cGK) inhibitor, Rp-8-Br-cGMPS (Rp)-treated wild-type 2-copy ( Npr 1 +/+ ) and gene-duplicated 4-copy ( Npr 1 ++/++ ) mice. Blood pressure (BP) was significantly higher in 0-copy mice (138.6 ± 3.1 mmHg) and lower in 4-copy mice (86.0 ± 2.8 mmHg) than 2-copy mice (102.2 ± 1.7 mmHg). Treatment with A71915 and Rp showed significant changes in BP in 2-copy mice but caused only small increase in 4-copy mice. We found a significant decrease in renal cGMP levels with diminished cGK activity in 0-copy mice (p<0.0001) as well as A71915-treated (p<0.001) and Rp-treated (p<0.05) 2-copy and 4-copy mice as compared with controls animals. While significant activation of p-Erk1/2 (3-fold), p-p38MAPK (4-fold), p21 Cip1 (6-fold), and p27 Kip1 (5-fold) occurred in 0-copy, A71915-treated 2-copy, and A71915-treated 4-copy mice but Rp treatment caused minimal changes compared to control mice. There were significant increases in the proinflammatory cytokines, including TNF-α (6-fold), and IL-6 (3-fold) and profibrotic cytokine TGF-β1 (4-fold) in plasma and kidneys of 0-copy and A791915-treated 2-copy mice, but less in A71915-treated 4-copy mice than controls. Progressive renal pathology, including fibrosis, mesangial matrix expansion, tubular hypertrophy, and perivascular infiltration were significantly scored in 0-copy and A71915-treated 2-copy mice, but did so minimally in 4-copy mice compared with controls. The present results suggest that Npr1 has a pivotal role in inhibiting the renal fibrosis and pathology and exerts renal protective effects through the cGMP/cGK axis by repressing the CDK inhibitors, p21 Cip1 and p27 Kip1 . This work was supported by NIH grant (HL062147).

The Importance of Natriuretic Peptides in Cardiometabolic Diseases

The natriuretic peptide (NP) system is composed of 3 distinct peptides (atrial natriuretic peptide or ANP, B-type natriuretic peptide or BNP, and C-type natriuretic peptide or CNP) and 3 receptors (natriuretic peptide receptor-A or NPR-A or particulate guanynyl cyclase-A natriuretic peptide receptor-B or NPR-B or particulate guanynyl cyclase-B, and natriuretic peptide receptor-C or NPR-C or clearance receptor). ANP and BNP function as defense mechanisms against ventricular stress and the deleterious effects of volume and pressure overload on the heart. Although the role of NPs in cardiovascular homeostasis has been extensively studied and well established, much remains uncertain about the signaling pathways in pathological states like heart failure, a state of impaired natriuretic peptide function. Elevated levels of ANP and BNP in heart failure correlate with disease severity and have a prognostic value. Synthetic ANP and BNP have been studied for their therapeutic role in hypertension and heart failure, and promising trials are under way. In recent years, the expression of ANP and BNP in human adipocytes has come to light. Through their role in promotion of adipocyte browning, lipolysis, lipid oxidation, and modulation of adipokine secretion, they have emerged as key regulators of energy consumption and metabolism. NPR-A signaling in skeletal muscles and adipocytes is emerging as pivotal to the maintenance of long-term insulin sensitivity, which is disrupted in obesity and reduced glucose-tolerance states. Genetic variants in the genes encoding for ANP and BNP have been associated with a favorable cardiometabolic profile. In this review, we discuss several pathways that have been proposed to explain the role of NPs as endocrine networkers. There is much to be explored about the therapeutic role of NPs in improving metabolic milieu.