Abstract
Human embryonic stem cell–derived cardiomyocytes develop pronounced hypertrophy in response to angiotensin-2, endothelin-1, and a selected mix of three fatty acids. All three of these responses are accompanied by increases in both basal cytoplasmic Ca2+ and diacylglycerol, quantified with the Ca2+ sensor Fluo-4 and a FRET-based diacylglycerol sensor expressed in these cardiomyocytes. The heart glycoside, ouabain (30 nM), and a recently developed inhibitor of diacylglycerol lipases, DO34 (1 μM), cause similar hypertrophy responses, and both responses are accompanied by equivalent increases of basal Ca2+ and diacylglycerol. These results together suggest that basal Ca2+ and diacylglycerol form a positive feedback signaling loop that promotes execution of cardiac growth programs in these human myocytes. Given that basal Ca2+ in myocytes depends strongly on the Na+ gradient, we also tested whether nanomolar ouabain concentrations might stimulate Na+/K+ pumps, as described by others, and thereby prevent hypertrophy. However, stimulatory effects of nanomolar ouabain (1.5 nM) were not verified on Na+/K+ pump currents in stem cell–derived myocytes, nor did nanomolar ouabain block hypertrophy induced by endothelin-1. Thus, low-dose ouabain is not a “protective” intervention under the conditions of these experiments in this human myocyte model. To summarize, the major aim of this study has been to characterize the progression of hypertrophy in human embryonic stem cell–derived cardiac myocytes in dependence on diacylglycerol and Na+ gradient changes, developing a case that positive feedback coupling between these mechanisms plays an important role in the initiation of hypertrophy programs.
Highlights
Pathological cardiac myocyte hypertrophy [20] is a common step in the progression of heart disease to cardiac failure, a major cause of death worldwide [66]
The major aim of this study has been to characterize the progression of hypertrophy in human embryonic stem cell– derived cardiac myocytes in dependence on diacylglycerol and Na+ gradient changes, developing a case that positive feedback coupling between these mechanisms plays an important role in the initiation of hypertrophy programs
Results human embryonic stem cell (hESC)-derived cardiomyocytes develop hypertrophy in response to AT-2 and ET-1 As shown in Fig. 2a, b, immunoblots revealed clear increases in β-MHC expression levels in cultures treated with 1 μM AT-2 or 25 pM ET-1 versus control cultures treated with vehicle, i.e., 0.1% distilled water, for 5 days
Summary
Pathological cardiac myocyte hypertrophy [20] is a common step in the progression of heart disease to cardiac failure, a major cause of death worldwide [66]. Signaling programs that promote hypertrophy are activated by multiple mechanical, metabolic, and humoral perturbations. Hypertrophic growth of myocytes is promoted by the engagement of overlapping, self-amplifying signaling mechanisms. An increase in DAG will increase basal Ca2+ in cardiac myocytes by multiple mechanisms, and an increase in basal Ca2+ can increase DAG by multiple mechanisms. Details of this coupling and the major signaling pathways leading to cardiac myocyte growth are summarized subsequently
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