Abstract
Pressure overload-induced cardiac stress induces left ventricular hypertrophy driven by increased cardiomyocyte mass. The increased energetic demand and cardiomyocyte size during hypertrophy necessitate increased fuel and oxygen delivery and stimulate angiogenesis in the left ventricular wall. We have previously shown that the transcriptional regulator steroid receptor coactivator-2 (SRC-2) controls activation of several key cardiac transcription factors and that SRC-2 loss results in extensive cardiac transcriptional remodeling. Pressure overload in mice lacking SRC-2 induces an abrogated hypertrophic response and decreases sustained cardiac function, but the cardiomyocyte-specific effects of SRC-2 in these changes are unknown. Here, we report that cardiomyocyte-specific loss of SRC-2 (SRC-2 CKO) results in a blunted hypertrophy accompanied by a rapid, progressive decrease in cardiac function. We found that SRC-2 CKO mice exhibit markedly decreased left ventricular vasculature in response to transverse aortic constriction, corresponding to decreased expression of the angiogenic factor VEGF. Of note, SRC-2 knockdown in cardiomyocytes decreased VEGF expression and secretion to levels sufficient to blunt in vitro tube formation and proliferation of endothelial cells. During pressure overload, both hypertrophic and hypoxic signals can stimulate angiogenesis, both of which stimulated SRC-2 expression in vitro Furthermore, SRC-2 coactivated the transcription factors GATA-binding protein 4 (GATA-4) and hypoxia-inducible factor (HIF)-1α and -2α in response to angiotensin II and hypoxia, respectively, which drive VEGF expression. These results suggest that SRC-2 coordinates cardiomyocyte secretion of VEGF downstream of the two major angiogenic stimuli occurring during pressure overload bridging both hypertrophic and hypoxia-stimulated paracrine signaling.
Highlights
Pressure overload–induced cardiac stress induces left ventricular hypertrophy driven by increased cardiomyocyte mass
Similar to what we observed previously for universal steroid receptor coactivator-2 (SRC-2) KO animals [9], loss of cardiomyocyte SRC-2 resulted in blunted hypertrophy, as measured by left ventricular wall thickness and cardiomyocyte size, and decreased function, as measured by ejection fraction and fractional shortening compared with WT mice (Fig. 1, A–C)
We present a novel regulator of cardiomyocyteinduced angiogenesis, SRC-2, which we postulate induces VEGF expression from both hypertrophic and hypoxic signaling pathways (Fig. 8)
Summary
Pressure overload–induced cardiac stress induces left ventricular hypertrophy driven by increased cardiomyocyte mass. SRC-2 coactivated the transcription factors GATA-binding protein 4 (GATA-4) and hypoxia-inducible factor (HIF)-1␣ and -2␣ in response to angiotensin II and hypoxia, respectively, which drive VEGF expression These results suggest that SRC-2 coordinates cardiomyocyte secretion of VEGF downstream of the two major angiogenic stimuli occur-. The growing cardiomyocytes send paracrine signals to induce angiogenesis, keeping the vasculature in proportion with the ventricle wall mass [1, 2] This hypertrophy-induced signaling is at least partially driven through activation of transcription factor GATA-4, which controls many genes involved with the cardiomyocyte growth, as well as VEGF production and secretion from the cardiomyocyte [3]. Our results suggest that SRC-2 is a novel upstream coordinator of cardiomyocyte-driven angiogenesis during cardiac stress, bridging both hypertrophic and hypoxic-stimulated paracrine signaling
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