Biology subjects

Takeuchi, L. M.

Publications and source records attributed to Takeuchi, L. M..

4 recordsLinked to original sources

bioRxiv2025

Cardiomyocyte-specific expression of HIF-1α mediates the cardioprotective effects of Growth Hormone-Releasing Hormone (GHRH)

Heart failure (HF) with preserved ejection fraction (HFpEF) carries a high mortality and remains a major therapeutic challenge. Effective, targeted therapies capable of reversing HFpEF pathophysiology are urgently needed. We previously demonstrated that activation of the cardiac growth hormone-releasing hormone (GHRH) pathway using high potency synthetic agonists of GHRH (GHRH-agonists: MR-356 and MR-409) improves the HFpEF phenotype in both large and small animal models, including in a murine model of cardiometabolic HFpEF (High fat diet + the nitric oxide synthase inhibitor L-NAME [HFD+L-NAME]). Here we sought to define the downstream signaling pathways responsible for this effect. A transcriptomic screen in human iPSC-derived cardiomyocytes (hiPSC-CMs) identified the hypoxia-inducible factor (HIF)-1 pathway as being activated by GHRH receptor (GHRHR) signaling, revealing an oxygen-independent mechanism of HIF-1 activation. Based on this finding, we investigated the interaction between the cardioprotective effects of the GHRH-agonist MR-356 and HIF-1 pathway activation in the murine HFD+L-NAME model of cardiometabolic HFpEF. We generated a cardiomyocyte-specific HIF-1 knockout (HIF-1CMKO) mouse line and demonstrated that our previously reported beneficial effects of GHRH-agonist administration were completely abolished in HIF-1CMKO mice. Together, these findings establish the GHRHR-HIF-1 axis as a central pathway integrating metabolic and contractile remodeling, suggesting that therapeutic targeting of this axis represents a novel disease-modifying approach to treating cardiometabolic HFpEF.

physiology↗

bioRxiv2022

Efficacy of a Growth Hormone-Releasing Hormone Agonist in a Murine Model of Cardiometabolic Heart Failure with Preserved Ejection Fraction

Heart failure (HF) with preserved ejection fraction (HFpEF) represents a major unmet medical need owing to its diverse pathophysiology and lack of effective therapies. Potent synthetic, agonists (MR-356 and MR409) of growth hormone-releasing hormone (GHRH) improve the phenotype of models of HF with reduced ejection fraction (HFrEF) and in cardiorenal models of HFpEF. Endogenous GHRH exhibits a broad range of regulatory influences in the cardiovascular (CV) system, aging and plays a role in several cardiometabolic conditions including obesity and diabetes. Whether agonists of GHRH can improve the phenotype of cardiometabolic HFpEF remains untested and unknown. Here we tested the hypothesis that MR-356 can mitigate/reverse the cardiometabolic HFpEF phenotype. C57BL6N mice received a high fat diet (HFD) plus the nitric oxide synthase inhibitor (L-NAME) for 9 weeks. After 5 weeks of HFD+L-NAME regimen, animals were randomized to receive daily injections of MR-356 or placebo during a 4-week period. Control animals received no HFD+L-NAME or agonist treatment. Our results showed the unique potential of MR-356 to treat several HFpEF-like features including cardiac hypertrophy, fibrosis, capillary rarefaction, and pulmonary congestion. MR-356 improved cardiac performance by improving diastolic function, global longitudinal strain (GLS), and exercise capacity. Importantly, the increased expression of cardiac pro-brain natriuretic peptide (pro-BNP), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor-A (VEGF-A) was restored to normal levels suggesting that MR-356 reduced myocardial stress associated with metabolic inflammation in HFpEF. Thus, agonists of GHRH may be an effective therapeutic strategy for the treatment of cardiometabolic HFpEF phenotype.

physiology↗

bioRxiv2020

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

BackgroundTherapies that improve morbidity and mortality in heart failure with preserved ejection fraction (HFpEF) are lacking. Growth hormone releasing hormone analogues (GHRH-A) reverse fibrosis and improve cardiac function in ischemic and non-ischemic animal models. We tested the hypothesis that GHRH-A treatment ameliorates chronic kidney disease (CKD)-induced HFpEF in a large animal model. MethodsFemale Yorkshire pigs (n=16) underwent 5/6 nephrectomy via renal artery embolization, which induced HFpEF, and 12-weeks later received daily subcutaneous injections of GHRH-A (n=8) or placebo (n=8). Kidney function, renal and cardiac MRI, pressure-volume loops, and electrical stimulation were assessed at baseline, 12-weeks, and 16-18 weeks post-embolization. ResultsThe CKD model was confirmed by increased creatinine and BUN. HFpEF was demonstrated at 12 weeks by maintenance of ejection fraction associated with increased left ventricular mass, relative wall thickening, end-diastolic pressure (EDP), end-diastolic pressure-volume relationship (EDPVR), and tau. After 6 weeks of treatment, diastolic function improved in the GHRH-A group, evidenced by normalization of EDP (p=0.03) associated with improved diastolic compliance as measured by EDP/EDV ratio (p=0.018). ConclusionA beneficial effect of GHRH-A in diastolic function was observed in a CKD large animal model that manifests the characteristics of HFpEF. These findings have important therapeutic implications for the HFpEF syndrome.

physiology↗

bioRxiv2020

Synthetic Agonist of Growth Hormone-Releasing Hormone as Novel Treatment for Heart Failure with Preserved Ejection Fraction

ObjectiveTo test the hypothesis that the activation of the growth hormone-releasing hormone (GHRH) receptor signaling pathway within the myocardium both prevents and reverses heart failure with preserved ejection fraction (HFpEF). BackgroundHFpEF is characterized by impaired myocardial relaxation, fibrosis and ventricular stiffness. Despite the rapidly increasing prevalence of HFpEF, no effective therapies have emerged. Synthetic agonists of the GHRH receptors reduce myocardial fibrosis, hypertrophy and improve performance, independently of the growth-hormone axis. MethodsWe generated a HFpEF-like phenotype with continuous infusion of angiotensin-II (Ang-II) in CD1 mice. Mice were injected with either vehicle or a potent synthetic agonist of the growth hormone-releasing hormone, MR-356. ResultsAng-II treated animals had diastolic dysfunction, ventricular hypertrophy, and normal ejection fraction and isolated cardiomyocytes (ex vivo) exhibited incomplete relaxation, depressed contractile responses and altered myofibrillar protein phosphorylation. Calcium handling mechanisms were disturbed in cardiomyocytes from mice with HFpEF. MR-356 both prevented and reversed the development of the pathological phenotype in vivo and ex vivo. ConclusionThese findings indicate that the GHRH receptor signaling pathway represents a new molecular target to counteract HFpEF-associated cardiomyocyte dysfunction by targeting myofilament phosphorylation. Accordingly, activation of the GHRH receptor with potent synthetic GHRH agonists may provide a novel therapeutic approach to management of the HFpEF syndrome. Condensed abstractHeart failure with preserved ejection fraction (HFpEF) is characterized by a remodeled myocardium conferring ventricular stiffness and diastolic dysfunction. There are no effective therapies. Agonists of growth hormone-releasing hormone (GHRH) receptors have beneficial effects on the heart. We hypothesize that activation of GHRH receptors suppresses this HFpEF phenotype. Treatment with a synthetic agonist of GHRH, prevented the development of the pathological phenotype in a murine model of HFpEF-induced by chronic angiotensin-II infusion. These findings indicate that activation of GHRH receptors represents a novel molecular strategy to counteract HFpEF-associated cardiomyocyte dysfunction and provide a potential approach to management of HFpEF syndrome. HighlightsO_LIA synthetic growth hormone-releasing hormone agonist (GHRH-A) prevents and reverses the pathological remodeling in a mouse model of HFpEF induced by infusion of low dose Ang II. C_LIO_LIGHRH-A improves intracellular calcium handling by reducing the sarcoplasmic reticulum calcium leakage and enhancing phospholamban phosphorylation. C_LIO_LIGHRH-A treatment prevents and reverses diastolic dysfunction by enhancing the rate of sarcomere re-lengthening. C_LIO_LIActivation of the GHRH receptor with the GHRH-A, MR-356, leads to targeting myofibrillar proteins and desensitizing myofilaments in response to calcium. C_LI

cell biology↗