PDF(Pubmed)
Abstract：
Chronically elevated neurohumoral drive, and particularly elevated adrenergic tone leading to β-adrenergic receptor (β-AR) overstimulation in cardiac myocytes, is a key mechanism involved in the progression of heart failure. β1-AR and β2-ARs are the two major subtypes of β-ARs present in the human heart, however, they elicit different or even opposite effects on cardiac function and hypertrophy. For example, chronic activation of β1ARs drives detrimental cardiac remodeling while β2AR signaling is protective. The underlying molecular mechanisms for cardiac protection through β2ARs remain unclear. Here we show that β2-AR protects against hypertrophy through inhibition of PLCε signaling at the Golgi apparatus. The mechanism for β2AR-mediated PLC inhibition requires internalization of β2AR, activation of Gi and Gβγ subunit signaling at endosomes and ERK activation. This pathway inhibits both angiotensin II and Golgi-β1-AR-mediated stimulation of phosphoinositide hydrolysis at the Golgi apparatus ultimately resulting in decreased PKD and HDAC5 phosphorylation and protection against cardiac hypertrophy. This reveals a mechanism for β2-AR antagonism of the PLCε pathway that may contribute to the known protective effects of β2-AR signaling on the development of heart failure.
摘要：
慢性升高的神经体液驱动，特别是肾上腺素能张力升高导致心肌细胞β-肾上腺素能受体（β-AR）过度刺激，是心力衰竭进展的关键机制。β1-AR和β2-AR是存在于人类心脏中的两种主要的β-AR亚型,然而,它们对心脏功能和肥大产生不同甚至相反的影响。例如,β1ARs的慢性激活导致有害的心脏重塑,而β2AR信号传导具有保护作用.通过β2ARs保护心脏的潜在分子机制仍不清楚。在这里，我们表明β2-AR通过抑制高尔基体的PLCε信号传导来防止肥大。β2AR介导的PLC抑制的机制需要β2AR的内化，核内体Gi和Gβγ亚基信号的激活和ERK激活。该途径抑制血管紧张素II和高尔基体-β1-AR介导的高尔基体上的磷酸肌醇水解的刺激,最终导致降低的PKD和HDAC5磷酸化和对心脏肥大的保护。这揭示了PLCs途径的β2-AR拮抗机制，该机制可能有助于β2-AR信号传导对心力衰竭发展的已知保护作用。
