A CD103+ Conventional Dendritic Cell Surveillance System Prevents Development of Overt Heart Failure during Subclinical Viral Myocarditis.

Innate and adaptive immune cells modulate heart failure pathogenesis during viral myocarditis, yet their identities and functions remain poorly defined. We utilized a combination of genetic fate mapping, parabiotic, transcriptional, and functional analyses and demonstrated that the heart contained two major conventional dendritic cell (cDC) subsets, CD103+ and CD11b+, which differentially relied on local proliferation and precursor recruitment to maintain their tissue residency. Following viral infection of the myocardium, cDCs accumulated in the heart coincident with monocyte infiltration and loss of resident reparative embryonic-derived cardiac macrophages. cDC depletion abrogated antigen-specific CD8+ T cell proliferative expansion, transforming subclinical cardiac injury to overt heart failure. These effects were mediated by CD103+ cDCs, which are dependent on the transcription factor BATF3 for their development. Collectively, our findings identified resident cardiac cDC subsets, defined their origins, and revealed an essential role for CD103+ cDCs in antigen-specific T cell responses during subclinical viral myocarditis.

TRB3 function in cardiac endoplasmic reticulum stress.

RATIONALE: Tribbles (TRB)3 is an intracellular pseudokinase that modulates the activity of several signal transduction cascades. TRB3 has been reported to inhibit the activity of Akt protein kinases. TRB3 gene expression is highly regulated in many cell types, and amino acid starvation, hypoxia, or endoplasmic reticulum (ER) stress promotes TRB3 expression in noncardiac cells. OBJECTIVE: The objective of this work was to examine TRB3 expression and function in cultured cardiac myocytes and in mouse heart. METHODS AND RESULTS: Agents that induced ER stress increased TRB3 expression in cultured cardiac myocytes while blocking insulin-stimulated Akt activation in these cells. Knockdown of TRB3 in cultured cardiac myocytes reversed the effects of ER stress on insulin signaling. Experimental myocardial infarction led to increased TRB3 expression in murine heart tissue in the infarct border zone suggesting that ER stress may play a role in pathological cardiac remodeling. Transgenic mice with cardiac-specific overexpression of TRB3 were generated and they exhibited normal contractile function but altered cardiac signal transduction and metabolism with reduced cardiac glucose oxidation rates. Transgenic TRB3 mice were also sensitized to infarct expansion and cardiac myocyte apoptosis in the infarct border zone after myocardial infarction. CONCLUSIONS: These results demonstrate that TRB3 induction is a significant aspect of the ER stress response in cardiac myocytes and that TRB3 antagonizes cardiac glucose metabolism and cardiac myocyte survival.

The 14-3-3tau phosphoserine-binding protein is required for cardiomyocyte survival.

14-3-3 family members are intracellular dimeric phosphoserine-binding proteins that regulate signal transduction, cell cycle, apoptotic, and metabolic cascades. Previous work with global 14-3-3 protein inhibitors suggested that these proteins play a critical role in antagonizing apoptotic cell death in response to provocative stimuli. To determine the specific role of one family member in apoptosis, mice were generated with targeted disruption of the 14-3-3tau gene. 14-3-3tau(-/-) mice did not survive embryonic development, but haploinsufficient mice appeared normal at birth and were fertile. Cultured adult cardiomyocytes derived from 14-3-3tau(+/-) mice were sensitized to apoptosis in response to hydrogen peroxide or UV irradiation. 14-3-3tau(+/-) mice were intolerant of experimental myocardial infarction and developed pathological ventricular remodeling with increased cardiomyocyte apoptosis. ASK1, c-jun NH(2)-terminal kinase, and p38 mitogen-activated protein kinase (MAPK) activation was increased, but extracellular signal-regulated kinase MAPK activation was reduced, in 14-3-3tau(+/-) cardiac tissue. Inhibition of p38 MAPK increased survival in 14-3-3tau(+/-) mice subjected to myocardial infarction. These results demonstrate that 14-3-3tau plays a critical antiapoptotic function in cardiomyocytes and that therapeutic agents that increase 14-3-3tau activity may be beneficial to patients with myocardial infarction.

Beta3 integrin deficiency promotes cardiac hypertrophy and inflammation.

Cardiac hypertrophy commonly develops in response to pressure overload and is associated with increased mortality. Mechanical stress in the heart can result in the activation of transmembrane integrin alphabeta heterodimers that are expressed in cardiomyocytes. Once activated, integrins stimulate focal adhesion kinase, Grb2, c-src, and other signaling molecules to promote cardiomyocyte growth and gene expression. Mechanical stress can also promote cardiac inflammation that may be mediated, in part, by the activation of integrins expressed in blood-borne cells. To address the role of one integrin, beta(3), in the pathogenesis of cardiac hypertrophy, beta(3)(-/-) mice were examined. beta(3)(-/-) Mice developed moderate spontaneous cardiac hypertrophy associated with systolic and diastolic dysfunction, and these abnormalities were exacerbated by transverse aortic constriction. In addition, beta(3)(-/-) mice developed mild cardiac inflammation with infiltrating macrophages at baseline that was markedly worsened by pressure overload. Bone marrow transplantation experiments showed that blood-borne cells were at least partially responsible for the cardiac hypertrophy and inflammation observed in beta(3)(-/-) mice. These results suggest that alpha(v)beta(3) expression in bone marrow has a generalized suppressive effect on cardiac inflammation.