Huntley Brenda K, Sandberg Sharon M, Noser Josh A, Cataliotti Alessandro, Redfield Margaret M, Matsuda Yuzuru, Burnett John C
Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, MN 55904, USA.
J Cell Physiol. 2006 Dec;209(3):943-9. doi: 10.1002/jcp.20793.
Cardiac remodeling involves the accumulation of extracellular matrix (ECM) proteins including fibronectin (FN). FN contains RGD motifs that bind integrins at DDX sequences allowing signaling from the ECM to the nucleus. We noted that the natriuretic peptide receptor A (NPR-A) sequence contains both RGD and DDX sequences. The goal of the current investigation was to determine potential interactions between FN and NPR-A on BNP induction of cGMP in cultured human cardiac fibroblasts (CFs). Further, we sought to determine whether a Mayo designed NPR-A specific RGD peptide could modify this interaction. Here we reconfirm the presence of all three natriuretic peptide receptors (NPR) in CFs. CFs plated on FN demonstrated a pronounced increase in cGMP production to BNP compared to non-coated plates. This production was also enhanced by the NPR-A specific RGD peptide, which further augmented FN associated cGMP production. Addition of HS-142-1, a NPR-A/B antagonist, abrogated the responses of BNP to both FN and the NPR-A specific RGD peptide. Finally, we defined a possible role for the NPR-C through non-cGMP mechanisms in mediating the anti-proliferative actions of BNP in CFs where the NPR-C antagonist cANF 4-28 but not HS-142-1 blocked BNP-mediated inhibition of proliferation of CFs. We conclude that NPR-A interacts with components of the ECM such as FN to enhance BNP activation of cGMP and that a small NPR-A specific RGD peptide augments this action of BNP with possible therapeutic implications. Lastly, the NPR-C may also have a role in mediating anti-proliferative actions of BNP in CFs.
心脏重塑涉及细胞外基质（ECM）蛋白的积累，包括纤连蛋白（FN）。FN含有RGD基序，可在DDX序列处与整合素结合，从而实现从ECM到细胞核的信号传导。我们注意到利钠肽受体A（NPR-A）序列同时包含RGD和DDX序列。本研究的目的是确定在培养的人心脏成纤维细胞（CFs）中，FN与NPR-A在BNP诱导cGMP过程中的潜在相互作用。此外，我们试图确定Mayo设计的NPR-A特异性RGD肽是否可以改变这种相互作用。在这里，我们再次证实CFs中存在所有三种利钠肽受体（NPR）。与未包被的平板相比，接种在FN上的CFs对BNP的cGMP生成有明显增加。这种生成也被NPR-A特异性RGD肽增强，该肽进一步增加了与FN相关的cGMP生成。添加NPR-A/B拮抗剂HS-142-1可消除BNP对FN和NPR-A特异性RGD肽的反应。最后，我们确定了NPR-C通过非cGMP机制在介导BNP对CFs的抗增殖作用中的可能作用，其中NPR-C拮抗剂cANF 4-28而非HS-142-1可阻断BNP介导的CFs增殖抑制。我们得出结论，NPR-A与ECM成分如FN相互作用，以增强BNP对cGMP的激活，并且一种小的NPR-A特异性RGD肽增强了BNP的这种作用，可能具有治疗意义。最后，NPR-C也可能在介导BNP对CFs的抗增殖作用中发挥作用。
