Cell based dATP delivery as a therapy for chronic heart failure.

Transplanted human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) improve ventricular performance when delivered acutely post-myocardial infarction but are ineffective in chronic myocardial infarction/heart failure. 2'-deoxy-ATP (dATP) activates cardiac myosin and potently increases contractility. Here we engineered hPSC-CMs to overexpress ribonucleotide reductase, the enzyme controlling dATP production. In vivo, dATP-producing CMs formed new myocardium that transferred dATP to host cardiomyocytes via gap junctions, increasing their dATP levels. Strikingly, when transplanted into chronically infarcted hearts, dATP-producing grafts increased left ventricular function, whereas heart failure worsened with wild-type grafts or vehicle injections. dATP-donor cells recipients had greater voluntary exercise, improved cardiac metabolism, reduced pulmonary congestion and pathological cardiac hypertrophy, and improved survival. This combination of remuscularization plus enhanced host contractility offers a novel approach to treating the chronically failing heart.

dATP elevation induces myocardial metabolic remodeling to support improved cardiac function.

Hallmark features of systolic heart failure are reduced contractility and impaired metabolic flexibility of the myocardium. Cardiomyocytes (CMs) with elevated deoxy ATP (dATP) via overexpression of ribonucleotide reductase (RNR) enzyme robustly improve contractility. However, the effect of dATP elevation on cardiac metabolism is unknown. Here, we developed proteolysis-resistant versions of RNR and demonstrate that elevation of dATP/ATP to ∼1% in CMs in a transgenic mouse (TgRRB) resulted in robust improvement of cardiac function. Pharmacological approaches showed that CMs with elevated dATP have greater basal respiratory rates by shifting myosin states to more active forms, independent of its isoform, in relaxed CMs. Targeted metabolomic profiling revealed a significant reprogramming towards oxidative phosphorylation in TgRRB-CMs. Higher cristae density and activity in the mitochondria of TgRRB-CMs improved respiratory capacity. Our results revealed a critical property of dATP to modulate myosin states to enhance contractility and induce metabolic flexibility to support improved function in CMs.

Crosstalk between FGF23- and angiotensin II-mediated Ca2+ signaling in pathological cardiac hypertrophy.

Heart failure (HF) manifestation and progression are driven by systemic activation of neuroendocrine signaling cascades, such as the renin-angiotensin aldosterone system (RAAS). Fibroblast growth factor 23 (FGF23), an endocrine hormone, is linked to HF and cardiovascular mortality. It is also a mediator of left-ventricular hypertrophy (LVH). In vivo, high circulating levels of FGF23 are associated with an altered systemic RAAS response. FGF23 is proposed to trigger pathological signaling mediated by Ca2+-regulated transcriptional pathways. In the present study, we investigated Ca2+-dependent signaling of FGF23 in ventricular cardiomyocytes and its association with angiotensin II (ATII). In neonatal rat ventricular myocytes (NRVMs), both ATII and FGF23 induced hypertrophy as observed by an increase in cell area and hypertrophic gene expression. Furthermore, FGF23 activates nuclear Ca2+-regulated CaMKII-HDAC4 pathway, similar to ATII. In addition to a global increase in cytoplasmic Ca2+, FGF23, like ATII, induced inositol 1, 4, 5-triphosphate (IP3)-induced Ca2+ release from the nucleoplasmic Ca2+ store, associated with cellular hypertrophy. Interestingly, ATII receptor antagonist, losartan, significantly attenuated FGF23-induced changes in Ca2+ homeostasis and cellular hypertrophy suggesting an involvement of ATII receptor-mediated signaling. In addition, application of FGF23 increased intracellular expression of ATII peptide and its secretion in NRVMs, confirming the participation of ATII. In conclusion, FGF23 and ATII share a common mechanism of IP3-nuclear Ca2+-dependent cardiomyocyte hypertrophy. FGF23-mediated cellular hypertrophy is associated with increased production and secretion of ATII by cardiomyocytes. These findings indicate a pathophysiological role of the cellular angiotensin system in FGF23-induced hypertrophy in ventricular cardiomyocytes.