Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure

Abstract

SignificancePathological cardiac hypertrophy, characterized by heart growth in response to pressure or volume overload, such as in the setting of hypertension, is the main risk factor for heart failure (HF). The identification of therapeutic strategies to prevent or reverse cardiac hypertrophy is therefore a priority for curing HF. It is known that growth hormone-releasing hormone (GHRH) displays cardioprotective functions; however, its therapeutic potential in hypertrophy and HF is unknown. Here we show that GHRH reduces cardiomyocyte hypertrophy in vitro through inhibition of hypertrophic pathways. In vivo, the GHRH analog MR-409 attenuates cardiac hypertrophy in mice subjected to transverse aortic constriction and improves cardiac function. These findings suggest therapeutic use of GHRH analogs for treatment of pathological cardiac hypertrophy and HF.

The therapeutic impact of human neonatal BMSC in a right ventricular pressure overload model in mice

“…Cardiac hypertrophy can be prevented by triggering cytokine release into the anti-hypertrophic pathway, as previously described [5,19]. According to Zhou et al, enhanced VEGFR-1 signaling is involved in cardiomyocyte hypertrophy and the PKG-1 pathway is likely to associate with VEGFR-1.…”

“…Thus, we suggested BMSC injection caused beneficial effects in alleviating cardiac hypertrophy by paracrine cytokine and VEGF expression might be the most important part. Researches have focused on the mechanism of hypertrophy and the anti-hypertrophic pathway, including cytokine cardiotrophin 1, growth hormone-releasing hormones, K v 4.2 mRNA expression upregulated by basic fibroblast growth factor, and the VEGF signaling pathway [19,37,38]. According to a previous study, the regression of cardiomyocyte hypertrophy was related to a VEGF-dependent signaling pathway, which was also linked to PKG-1 activation [5].…”

Effectiveness of Growth Hormone–Releasing Hormone Agonists (GHRH-A) in Chronic Kidney Disease-Induced Heart Failure with Preserved Ejection Fraction

“…Together these preclinical findings support ongoing translational development of this class of agents for human HFpEF. HFpEF likely occur through multiple mechanisms 15 , including anti-apoptotic effects via inhibition of ERK1/2 and PI3K/Akt signaling associated with elevated Blc-2 and reduced Bax:Bcl-2 6 , stimulation of cardiac progenitor proliferation 6,16 , inhibition of hypertrophy, including Gq signaling and downstream pathways 17 , reduced inflammation, a major HFpEF-characteristic, specifically plasma levels of IL-2, IL-6 and TNF-α 6 , reduced expression of pro-fibrotic pathways genes 6 , and better organized collagen deposition 6 . In a mouse model of HFpEF, GHRH-A inhibited cardiomyocyte sarcomere and contractile dysfunction, preventing Ca 2+ leak from the sarcoplasmic reticulum and improving sarcomere relaxation and calcium handling 9 .…”

Single-cell RNA-sequencing Unravels Heterogeneity of Cardiomyocytes and Signaling Pathways in Pressure Overload

“…Pressure overload could promote apoptosis of cardiomyocytes [34]. Several drugs (such as Tamarixetin [35], growth hormone releasing hormone [36] and Resveratrol [5]) have been found to inhibit cardiomyocyte apoptosis by targeting apoptosis-related genes. Increasing evidence suggests that cardiac ion channels such as voltage-gated Ca 2+ , Na + , K + channels are regulated by multiple factors and their loss of control could induce arrhythmias and myocardial systolic disorders [37].…”