Autophagy, an evolutionarily conserved process for the bulk degradation of cytoplasmic components, serves as a cell survival mechanism in starving cells. Although altered autophagy has been observed in various heart diseases, including cardiac hypertrophy and heart failure, it remains unclear whether autophagy plays a beneficial or detrimental role in the heart. Here, we report that the cardiac-specific loss of autophagy causes cardiomyopathy in mice. In adult mice, temporally controlled cardiac-specific deficiency of Atg5 (autophagy-related 5), a protein required for autophagy, led to cardiac hypertrophy, left ventricular dilatation and contractile dysfunction, accompanied by increased levels of ubiquitination. Furthermore, Atg5-deficient hearts showed disorganized sarcomere structure and mitochondrial misalignment and aggregation. On the other hand, cardiac-specific deficiency of Atg5 early in cardiogenesis showed no such cardiac phenotypes under baseline conditions, but developed cardiac dysfunction and left ventricular dilatation one week after treatment with pressure overload. These results indicate that constitutive autophagy in the heart under baseline conditions is a homeostatic mechanism for maintaining cardiomyocyte size and global cardiac structure and function, and that upregulation of autophagy in failing hearts is an adaptive response for protecting cells from hemodynamic stress.

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Using pharmacological activation and genetic ablation of β2-adrenergic receptors (β2ARs) in mice, Nakai et al. show that β2ARs expressed on lymphocytes can regulate egress of these cells from lymph nodes, while altering the responsiveness of chemokine receptors CCR7 and CXCR4. They identify that β2ARs can physically interact with these chemokine receptors. And, in mouse models of T cell–mediated inflammation, β2AR-mediated signals are shown to inhibit trafficking of antigen-primed T cells, reducing their numbers in inflamed peripheral tissues.

The molecular mechanism for the transition from cardiac hypertrophy, an adaptive response to biomechanical stress, to heart failure is poorly understood. The mitogen-activated protein kinase p38␣ is a key component of stress response pathways in various types of cells. In this study, we attempted to explore the in vivo physiological functions of p38␣ in hearts. First, we generated mice with floxed p38␣ alleles and crossbred them with mice expressing the Cre recombinase under the control of the ␣-myosin heavy-chain promoter to obtain cardiac-specific p38␣ knockout mice. These cardiac-specific p38␣ knockout mice were born normally, developed to adulthood, were fertile, exhibited a normal life span, and displayed normal global cardiac structure and function. In response to pressure overload to the left ventricle, they developed significant levels of cardiac hypertrophy, as seen in controls, but also developed cardiac dysfunction and heart dilatation. This abnormal response to pressure overload was accompanied by massive cardiac fibrosis and the appearance of apoptotic cardiomyocytes. These results demonstrate that p38␣ plays a critical role in the cardiomyocyte survival pathway in response to pressure overload, while cardiac hypertrophic growth is unaffected despite its dramatic down-regulation.

Suzuki et al. show that neural inputs to β2-adrenergic receptors expressed on lymphocytes generate the diurnal variation in the frequency of lymphocyte egress from lymph nodes, which is reflected in the magnitude of the adaptive immune response.