␣1-Adrenergic receptors mediate several biological effects of catecholamines, including the regulation of myocyte growth and contractility and transcriptional regulation of the atrial natriuretic factor (ANF) gene whose promoter contains an ␣1-adrenergic response element. The nuclear pathways and effectors that link receptor activation to genetic changes remain poorly understood. Here, we describe the isolation by the yeast one-hybrid system of a cardiac cDNA encoding a novel nuclear zinc finger protein, Zfp260, belonging to the Krüppel family of transcriptional regulators. Zfp260 is highly expressed in the embryonic heart but is downregulated during postnatal development. Functional studies indicate that Zfp260 is a transcriptional activator of ANF and a cofactor for GATA-4, a key cardiac regulator. Knockdown of Zfp260 in cardiac cells decreases endogenous ANF gene expression and abrogates its response to ␣1-adrenergic stimulation. Interestingly, Zfp260 transcripts are induced by ␣1-adrenergic agonists and are elevated in genetic models of hypertension and cardiac hypertrophy. The data identify Zfp260 as a novel transcriptional regulator in normal and pathological heart development and a nuclear effector of ␣1-adrenergic signaling.The endogenous catecholamines epinephrine and norepinephrine are key regulators of numerous physiologic functions, including learning, memory, and cardiovascular and endocrine homeostasis. Their dysregulation has been implicated in human conditions such as depression and addiction and in cardiovascular and metabolic diseases. Their effects are mediated by three classes of adrenergic receptors (ARs), ␤, ␣1, and ␣2, each comprised of three distinct gene products. They all belong to the superfamily of seven transmembrane G-protein-coupled receptors. ␣1-ARs are critical for a variety of catecholamine actions such as the control of blood pressure, smooth muscle contraction, myocardial function, and glycogenolysis. The importance of ␣1-ARs in physiology and pathophysiology is evidenced by the wide clinical use of ␣1-AR agonists and antagonists for the treatment of cardiovascular disease, flu and allergy symptoms, and benign prostate hyperplasia (40, 43). Paradoxically, the molecular mechanisms underlying ␣1-AR action remain undefined.Historically, the role of ␣1-ARs in different biologic systems was largely inferred from pharmacologic studies, but the development of transgenic mice with targeted deletion or overexpression of specific ␣1-AR subtypes has further confirmed the essential role of specific ␣1-ARs in regulation of physiologic processes (reviewed in references 40 and 44). For example, ␣1-null mice rapidly develop hyperinsulinemia, insulin resistance, and obesity in response to high-fat feeding, confirming the important role of ␣1-AR in the regulation of glucose homeostasis (7). The use of genetically altered mice also confirmed the essential role of ␣1-ARs in mediating the effects of some psychostimulants and opiates and, more generally, their involvement in the regulation of vario...