Rasmussen Helge H, Figtree Gemma
University of Sydney and Department of Cardiology, Royal North Shore Hospital, Sydney, NSW.
Crit Care Resusc. 2007 Dec;9(4):364-9.
Understanding the cellular and molecular biology of heart failure is essential to developing targeted and effective treatment. Investigators are divided in their belief regarding the primary abnormality and whether it lies in dysregulation of neurohormonal signalling; nitric oxide synthesis and oxidative stress; cellular energy supply; or cellular ions. Our research demonstrates that these independently studied pathways are, in fact, closely interrelated. The Na+-K+ pump is critical in the determination of intracellular sodium levels, which are elevated in heart failure. Drug therapies have been developed targeting the neurohormonal abnormalities seen in the clinical syndrome of heart failure. We have examined the effect of many of these medications on the activity of the Na+-K+ pump and observed a perfect correlation between the ability of the treatment to stimulate the pump and its clinical outcome. This is illustrated by the stimulation of the pump by inhibition of the renin- angiotensin signalling pathway, and by aldosterone antagonists. We have also examined the role of reactive oxygen species as mediators of angiotensin and adrenergic regulation of the pump, demonstrating that intracellular pathways activated by Beta(1)/Beta(2)-adrenoceptors and the angiotensin II type 1 receptor converge, with both activating NAD(P)H oxidase and inhibiting the Na+-K+ pump via oxidative stress. In contrast, targeted stimulation of the Beta(3)-receptor resulted in nitric oxide-dependent pump stimulation in vitro, and improvements in left ventricular function in a large-animal heart failure model. Further characterisation of the intricate pathways involved in the hormonal regulation of the myocyte and its response to heart failure may aid in specific targeting of therapy.
了解心力衰竭的细胞和分子生物学对于开发有针对性的有效治疗方法至关重要。研究人员对于原发性异常及其所在位置存在分歧，原发性异常是在于神经激素信号传导失调、一氧化氮合成和氧化应激、细胞能量供应还是细胞离子。我们的研究表明，这些独立研究的途径实际上密切相关。钠钾泵在决定细胞内钠水平方面至关重要，而细胞内钠水平在心力衰竭时会升高。已经开发出针对心力衰竭临床综合征中所见神经激素异常的药物疗法。我们研究了其中许多药物对钠钾泵活性的影响，并观察到治疗刺激泵的能力与其临床结果之间存在完美的相关性。肾素 - 血管紧张素信号通路的抑制以及醛固酮拮抗剂对泵的刺激就说明了这一点。我们还研究了活性氧作为血管紧张素和肾上腺素能对泵调节的介质的作用，证明由β(1)/β(2) - 肾上腺素能受体和1型血管紧张素II受体激活的细胞内途径会汇聚，二者均通过氧化应激激活NAD(P)H氧化酶并抑制钠钾泵。相比之下，β(3) - 受体的靶向刺激在体外导致了一氧化氮依赖性的泵刺激，并在大型动物心力衰竭模型中改善了左心室功能。对涉及心肌细胞激素调节及其对心力衰竭反应的复杂途径的进一步表征可能有助于治疗的特异性靶向。
