The beneficial effects of agonists of growth hormone-releasing hormone receptor (GHRH-R) in heart failure models are associated with an increase in the number of ckit + cardiac stem cells (CSCs). The goal of the present study was to determine the presence of GHRH-R in CSCs, the effect of GHRH-R agonists on their proliferation and survival, and the mechanisms involved. We investigated the expression of GHRH-R in CSCs of different species and the effect of GHRH-R agonists on their cell proliferation and survival. GHRH-R is expressed in ckit + CSCs isolated from mouse, rat, and pig. Treatment of porcine CSCs with the GHRH-R agonist JI-38 significantly increased the rate of cell division. Similar results were observed with other GHRH-R agonists, MR-356 and MR-409. JI-38 exerted a protective effect on survival of porcine CSCs under conditions of oxidative stress induced by exposure to hydrogen peroxide. Treatment with JI-38 before exposure to peroxide significantly reduced cell death. A similar effect was observed with MR-356. Addition of GHRH-R agonists to porcine CSCs induced activation of ERK and AKT pathways as determined by increased expression of phospho-ERK and phospho-AKT. Inhibitors of ERK and AKT pathways completely reversed the effect of GHRH-R agonists on CSC proliferation. Our findings extend the observations of the expression of GHRH-R by CSCs and demonstrate that GHRH-R agonists have a direct effect on proliferation and survival of CSCs. These results support the therapeutic use of GHRH-R agonists for stimulating endogenous mechanisms for myocardial repair or for preconditioning of stem cells before transplantation.cardiac stem cells | growth hormone-releasing hormone | agonists | cell proliferation | cell survival

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Background: Our group has previously shown that growth hormone releasing hormone receptor agonists (GHRHR-A) improve cardiac performance in heart failure models and reverse remodeling. This effect was associated with an increase in the number of c-kit+ cardiac stem cells (CSCs), suggesting that this agonist might have an effect on these cells. Methods and Results: We investigated the expression of GHRH receptor (GHRHR) in CSCs of different species by flow cytometry analysis. GHRH-R is expressed in 96-98% of CSCs isolated from mouse, rat and porcine. Results were compared to GHRHR expression in HeLa and MCF7, and T47D cell lines, positive and negative controls, respectively. To determine if GHRHR activation can improve CSCs self-renewal, we tested the effect of agonists on porcine CSCs proliferation. The rate of cell division was increased 2-fold with JI38 (GHRHR-A) treatment (3.4 ± 0.7) vs. vehicle control (1.7 ± 0.2) (p<0.05). Pre-treatment of CSCs with the GHRHR antagonist MIA-602, showed a trend toward reversal of the JI38 agonistic effect on proliferation rate (2.2 ± 0.6). These studies were further extended to other GHRHR agonists. In addition to JI38, MR356 and MR409, both of which showed significant increase in CSCs proliferation relative to vehicle control, by 20 ± 5.7%, 37 ± 8.5% and 36 ± 12.2%, respectively (p<0.05). The protective effect of JI38 on porcine CSCs survival was determined under oxidative stress generated by hydrogen peroxide exposure. Pre-treatment of CSCs with JI38 prior to peroxide exposure significantly reduced cell death by 33 ± 2.2% (p<0.02). Similar effects were observed for MR356, which decreased cell death by 12 ± 8.6% (p<0.03). Furthermore, we found that the effect of GHRHR-A on CSCs proliferation was completely reversed by inhibitors of the ERK, PI3K and Akt pathways (p<0.05). Conclusion: These findings confirm for the first time the expression of GHRHR in CSCs. GHRHR-A promotes CSCs proliferation and enhance survival. GHRHR-A effects on CSCs proliferation are mediated through activation of ERK, PI3K and AKT pathways. Accordingly, activation of GHRHR signaling pathways represents a novel therapeutic approach to protect and stimulate endogenous CSC population, promoting cardiac repair.

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For the management of hydrocephalus with ventricular cerebrospinal fluid (CSF) shunting, multiple therapeutic options are available. Among these routes, the most commonly used are ventriculo-peritoneal, ventriculo-atrial, and ventriculo-pleural, while ventriculo-cholecystic is a less common option. Although ventriculo-peritoneal is accepted as the first option, ventriculo-cholecystic shunting may be performed in patients who are poor candidates for other routes of shunt placement. Open cholecystic shunt placement may be contraindicated in patients who have undergone previous surgeries or other comorbidities. Here, we present the case of a 25-year-old female with a complex medical history who presented with a posterior fossa intraparenchymal hemorrhage and subsequent hydrocephalus. She was unable to undergo a ventriculo-peritoneal, atrial, or pleural shunt placement, and thus, a cholecystic shunt placement was chosen. Due to a history of previous surgeries and comorbidities as well as a large volume of idiopathic and recurrent ascites, open placement was contraindicated in this patient. To the best of our knowledge, we present the first successful adult case of a minimally invasive ventriculo-cholecystic shunt placement under ultrasound and fluoroscopic guidance.