Abstract
ABSTRACTCardiac hypertrophy is an important and independent risk factor for the development of heart failure. To better understand the mechanisms and regulatory pathways involved in cardiac hypertrophy, there is a need for improved in vitro models. In this study, we investigated how hypertrophic stimulation affected human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). The cells were stimulated with endothelin-1 (ET-1) for 8, 24, 48, 72, or 96 h. Parameters including cell size, ANP-, proBNP-, and lactate concentration were analyzed. Moreover, transcriptional profiling using RNA-sequencing was performed to identify differentially expressed genes following ET-1 stimulation. The results show that the CMs increase in size by approximately 13% when exposed to ET-1 in parallel to increases in ANP and proBNP protein and mRNA levels. Furthermore, the lactate concentration in the media was increased indicating that the CMs consume more glucose, a hallmark of cardiac hypertrophy. Using RNA-seq, a hypertrophic gene expression pattern was also observed in the stimulated CMs. Taken together, these results show that hiPSC-derived CMs stimulated with ET-1 display a hypertrophic response. The results from this study also provide new molecular insights about the underlying mechanisms of cardiac hypertrophy and may help accelerate the development of new drugs against this condition.
Highlights
Cardiac hypertrophy is characterized by an enlargement of the heart due to an increase in size of the cardiomyocytes (CMs) (Frey et al, 2004)
Pathological hypertrophy, on the other hand, may progress to heart failure if the stimuli persists for an extended time and is a maladaptive decompensatory condition where the heart increases in size due to alteration in several signaling pathways (Pham et al, 2000; Rockman et al, 2002; Bueno et al, 2000)
These alterations result in pathological hypertrophy including adverse gene expression profile, increase in ANP and BNP protein levels, and increased lactate production due to a higher glucose consumption (Frey and Olson, 2003; Almeida et al, 2003; Kolwicz and Tian, 2011)
Summary
Cardiac hypertrophy is characterized by an enlargement of the heart due to an increase in size of the cardiomyocytes (CMs) (Frey et al, 2004). Pathological hypertrophy, on the other hand, may progress to heart failure if the stimuli persists for an extended time and is a maladaptive decompensatory condition where the heart increases in size due to alteration in several signaling pathways (Pham et al, 2000; Rockman et al, 2002; Bueno et al, 2000) These alterations result in pathological hypertrophy including adverse gene expression profile, increase in ANP and BNP protein levels, and increased lactate production due to a higher glucose consumption (Frey and Olson, 2003; Almeida et al, 2003; Kolwicz and Tian, 2011). Novel technologies, based on human stem cells, could offer clinically relevant in vitro-based alternatives
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