Ablating a Cardiac Protein

Abstract

The article describes, for the first time, the targeted ablation of a cardiac protein that biochemical and physiological approaches had indicated as being important for the heart’s response to β-adrenergic stimulation. The article brought the technology of gene targeting to the heart and helped establish the mouse as a useful and relevant model for studying normal and abnormal cardiovascular function. During much of the 20th century, cardiovascular research was firmly based on the 2 pillars of biochemistry and physiology. Biochemistry used reductionist approaches, dissecting a system into its component parts and studying them in isolated or reconstituted systems. Physiology, on the contrary, centered on intact animals, organs, and tissues in an attempt to understand how those systems functioned within the whole body context. These 2 disciplines brought many advances to cardiovascular research, but the ambiguous demonstrations needed to establish necessity, sufficiency, and causality remained elusive for many important cardiac proteins and functions. What is sufficient to mediate important short-term and long-term effects on cardiovascular function and adaptation? What is necessary? How might one establish direct causation in a whole animal context, in terms of a particular cardiac protein leading to disease or affecting muscle function? To address these types of questions, investigators had long used the tools of genetics in lower organisms to target a particular gene, either enhancing or ablating its function. Using these precise genetic tools, the subsequent effects on protein function could be measured in isolated cell types, tissues, organs, and the whole animal. Unfortunately, these earlier studies were largely restricted to genetically accessible systems such as worms, bacteriophages and virus, bacteria, yeasts, molds, and flies, whose cardiovascular systems were either absent or far removed from the 4-chambered, mammalian heart. Much of the seminal biochemical work establishing the importance of phospholamban (PLN) and its interactions with the …