The molecular clock mechanism underlies circadian rhythms and is defined by a transcription-translation feedback loop. Bmal1 encodes a core molecular clock transcription factor. Germline Bmal1 knockout mice show a loss of circadian variation in heart rate and blood pressure, and they develop dilated cardiomyopathy. We tested the role of the molecular clock in adult cardiomyocytes by generating mice that allow for the inducible cardiomyocyte-specific deletion of Bmal1 (iCS⌬Bmal1). ECG telemetry showed that cardiomyocyte-specific deletion of Bmal1 (iCS⌬Bmal1 Ϫ/Ϫ ) in adult mice slowed heart rate, prolonged RR and QRS intervals, and increased episodes of arrhythmia. Moreover, isolated iCS⌬Bmal1 Ϫ/Ϫ hearts were more susceptible to arrhythmia during electromechanical stimulation. Examination of candidate cardiac ion channel genes showed that Scn5a, which encodes the principle cardiac voltage-gated Na ϩ channel (NaV1.5), was circadianly expressed in control mouse and rat hearts but not in iCS⌬Bmal1 Ϫ/Ϫ hearts. In vitro studies confirmed circadian expression of a human Scn5a promoter-luciferase reporter construct and determined that overexpression of clock factors transactivated the Scn5a promoter. Loss of Scn5a circadian expression in iCS⌬Bmal1 Ϫ/Ϫ hearts was associated with decreased levels of NaV1.5 and Na ϩ current in ventricular myocytes. We conclude that disruption of the molecular clock in the adult heart slows heart rate, increases arrhythmias, and decreases the functional expression of Scn5a. These findings suggest a potential link between environmental factors that alter the cardiomyocyte molecular clock and factors that influence arrhythmia susceptibility in humans. cardiac excitability; circadian; heart; ion channels; Scn5a; Na ϩ current CIRCADIAN RHYTHMS are approximate 24-h cycles in biology. These rhythms are present at the systems level, the tissue level, the single cell and molecular levels (16,33,34,38). There are several examples of circadian rhythms in the cardiovascular system, with heart rate, blood pressure, and substrate metabolism exhibiting distinct oscillations over time of day (12,13,40,41). The mechanism that underlies circadian function is the molecular clock. The molecular clock is defined, in a simple way, by a transcription-translation feedback mechanism that is composed of the core clock genes Clock, Bmal1, Per1, Per2, Cry1, and Cry2. CLOCK and BMAL1 are transcription factors that heterodimerize and activate transcription of Per1, Per2, Cry1, and Cry2. PER1, PER2, CRY1, and CRY2 form multimers in the cytoplasm of the cell, translocate to the nucleus, and act to inhibit CLOCK:BMAL1 function. This cycle takes ϳ24 h and is the fundamental mechanism underlying circadian rhythms. Components of the core clock have also been shown to regulate the expression of genes outside the clock mechanism, and these genes are designated as clock-controlled genes (CCGs). CCGs often encode transcription factors or proteins that control rate-limiting steps in cell physiology (42).In the last 8 years, resear...

Rationale: The Xin repeat-containing proteins mXin␣ and mXin␤ localize to the intercalated disc of mouse heart and are implicated in cardiac development and function. The mXin␣ directly interacts with ␤-catenin, p120-catenin, and actin filaments. Ablation of mXin␣ results in adult late-onset cardiomyopathy with conduction defects. An upregulation of the mXin␤ in mXin␣-deficient hearts suggests a partial compensation. Objective: The essential roles of mXin␤ in cardiac development and intercalated disc maturation were investigated. Methods and Results: Ablation of mXin␤ led to abnormal heart shape, ventricular septal defects, severe growth retardation, and postnatal lethality with no upregulation of the mXin␣. Postnatal upregulation of mXin␤ in wild-type hearts, as well as altered apoptosis and proliferation in mXin␤-null hearts, suggests that mXin␤ is required for postnatal heart remodeling. The mXin␤-null hearts exhibited a misorganized myocardium as detected by histological and electron microscopic studies and an impaired diastolic function, as suggested by echocardiography and a delay in switching off the slow skeletal troponin I. Loss of mXin␤ resulted in the failure of forming mature intercalated discs and the mislocalization of mXin␣ and N-cadherin. The mXin␤-null hearts showed upregulation of active Stat3 (signal transducer and activator of transcription 3) and downregulation of the activities of Rac1, insulin-like growth factor 1 receptor, protein kinase B, and extracellular signal-regulated kinases 1 and 2. Conclusions: These findings identify not only an essential role of mXin␤ in the intercalated disc maturation but also mechanisms of mXin␤ modulating N-cadherin-mediated adhesion signaling and its crosstalk signaling for postnatal heart growth and animal survival. (Circ Res. 2010;106:1468-1478.)Key Words: N-cadherin-mediated adhesion signaling Ⅲ Xin repeat-containing protein Ⅲ intercalated disc maturation Ⅲ diastolic dysfunction Ⅲ postnatal heart growth A regulatory network of transcription factors is known to control cardiac morphogenesis. Although the core players in this network are highly conserved, from organisms with simple heart-like cells to those with complex four-chambered hearts, it has been theorized and proven that expansion of this regulatory network by adding new transcription factors is a major force for the heart to evolve new structures. 1,2 However, the addition of new transcription factors can only be a part of the mechanism underlying the formation of complex hearts. The transcription factors must act through their downstream targets, which are directly involved in cardiac morphogenesis, growth and function. However, our inventory of such downstream targets remains incomplete.The Xin repeat-containing proteins from chicken and mouse hearts (cXin and mXin␣, respectively) were first identified as a target of the Nkx2.5-Mef2C pathway. 3,4 Another mouse Xin protein, mXin␤ (or myomaxin), has been subsequently identified as a Mef2A downstream target. 5 Evolutionary studies suggest t...

Endorheic basins around the world are suffering from water and ecosystem crisis. To pursue sustainable development, quantifying the hydrological cycle is fundamentally important. However, knowledge gaps exist in how climate change and human activities influence the hydrological cycle in endorheic basins. We used an integrated ecohydrological model, in combination with systematic observations, to analyze the hydrological cycle in the Heihe River Basin, a typical endorheic basin in arid region of China. The water budget was closed for different landscapes, river channel sections, and irrigation districts of the basin from 2001 to 2012. The results showed that climate warming, which has led to greater precipitation, snowmelt, glacier melt, and runoff, is a favorable factor in alleviating water scarcity. Human activities, including ecological water diversion, cropland expansion, and groundwater overexploitation, have both positive and negative effects. The natural oasis ecosystem has been restored considerably, but the overuse of water in midstream and the use of environmental flow for agriculture in downstream have exacerbated the water stress, resulting in unfavorable changes in surface‐ground water interactions and raising concerns regarding how to fairly allocate water resources. Our results suggest that the water resource management in the region should be adjusted to adapt to a changing hydrological cycle, cropland area must be reduced, and the abstraction of groundwater must be controlled. To foster long‐term benefits, water conflicts should be handled from a broad socioeconomic perspective. The findings can provide useful information on endorheic basins to policy makers and stakeholders around the world.