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Cardiovascular Protective vs. Anti‐Cancer Properties: Novel Actions of the AT2R Agonist, NP‐6A4
Author(s) -
Belenchia Anthony M,
Beauparlant Paige,
Mahmood Abuzar,
Bajwa Jamal,
Zhang Qiong,
Khare Sharad,
Pulakat Lakshmi
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb680
Subject(s) - agonist , angiotensin ii , neurite , receptor , neuroprotection , pharmacology , sh sy5y , cell culture , chemistry , endocrinology , medicine , in vitro , biology , biochemistry , genetics , neuroblastoma
Angiotensin II receptor AT2R is a member of the anti‐inflammatory branch of Renin‐Angiotensin System that exerts vasodilative, cardioreparative, and neuroprotective effects. AT2R agonist therapy represents a potential approach to treating cardiac repair following ischemia. However, low level expression of AT2R encoded by the Agtr2 gene in adult tissues present challenges in using AT2R activation as a therapy for cardiovascular protection. AT2R agonists such as CGP42112A (a peptide agonist) or C21 (a non‐peptide agonist) are not reported to increase Agtr2 expression. We previously reported that NP‐6A4, a novel peptide agonist of the AT2R (from Novopyxis Inc), could improve cell survival and viability of serum‐starved mouse cardiomyocyte HL‐1 cells and primary human coronary artery vascular smooth muscle cells (hCAVSMC). Here we report that treatment of hCAVSMC with NP‐6A4 (1μM) for 48 hours resulted in significant increases in Agtr2 expression (up to 4 fold; p <0.05). To determine whether NP‐6A4 could increase Agtr2 expression in non‐vascular cells, we investigated the effect of NP‐6A4 on human dopaminergic neuronal cell line SH‐SY5Y and the human hepatocellular carcinoma cell line, HepG2. SH‐SY5Y cells are an in vitro model of neuronal function and differentiation. NP‐6A4 treatment (48 hours) increased Agtr2 expression in SH‐SY5Y cells (2‐fold; p <0.05). Similarly NP‐6A4 treatment of HepG2 cells (48 hours) resulted in a 3.2‐fold increase in Agtr2 expression ( p <0.05). Interestingly, while NP‐6A4 improved neurite outgrowth of SH‐SY5Y cells, it suppressed cell growth of HepG2 cells. HepG2 cell growth and viability was determined by xCELLigence real‐time cell analyzer (RTCA), which provides a single cell index (CI) value based on cell size, proliferation, and adhesion. HepG2 cells treated with NP‐6A4 showed a significant reduction in CI compared to untreated cells ( p <0.05). Moreover, NP‐6A4 treatment entirely repressed proliferation of HepG2 cells, as determined by MTS assay ( p <0.05). To further determine whether NP‐6A4 could inhibit growth of other cancer cell lines, we investigated the effect of NP‐6A4 on the human breast adenocarcinoma cell line MCF‐7. Treatment of MCF‐7 cells with NP‐6A4 (48 hours) significantly reduced both their CI (determined by RTCA) and cell proliferation (determined by MTS assay) compared to untreated cells ( p <0.05). These data demonstrate that in addition to the well‐documented cardioprotective effects of AT2R agonists, NP‐6A4 is capable of inhibiting carcinoma cell growth—highlighting its unique capabilities as an onco‐cardiovascular therapeutic.