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Articles by J. D Molkentin
Total Records ( 3 ) for J. D Molkentin
  J Qian , X Ren , X Wang , P Zhang , W. K Jones , J. D Molkentin , G. C Fan and E. G. Kranias

Rationale: The levels of a small heat shock protein (Hsp)20 and its phosphorylation are increased on ischemic insults, and overexpression of Hsp20 protects the heart against ischemia/reperfusion injury. However, the mechanism underlying cardioprotection of Hsp20 and especially the role of its phosphorylation in regulating ischemia/reperfusion–induced autophagy, apoptosis, and necrosis remain to be clarified.

Objective: Herein, we generated a cardiac-specific overexpression model, carrying nonphosphorylatable Hsp20, where serine 16 was substituted with alanine (Hsp20S16A). By subjecting this model to ischemia/reperfusion, we addressed whether: (1) the cardioprotective effects of Hsp20 are associated with serine 16 phosphorylation; (2) blockade of Hsp20 phosphorylation influences the balance between autophagy and cell death; and (3) the aggregation pattern of Hsp20 is altered by its phosphorylation.

Methods and Results: Our results demonstrated that Hsp20S16A hearts were more sensitive to ischemia/reperfusion injury, evidenced by lower recovery of contractile function and increased necrosis and apoptosis, compared with non-TG hearts. Interestingly, autophagy was activated in non-TG hearts but significantly inhibited in Hsp20S16A hearts following ischemia/reperfusion. Accordingly, pretreatment of Hsp20S16A hearts with rapamycin, an activator of autophagy, resulted in improvement of functional recovery, compared with saline-treated Hsp20S16A hearts. Furthermore, on ischemia/reperfusion, the oligomerization pattern of Hsp20 appeared to shift to higher aggregates in Hsp20S16A hearts.

Conclusions: Collectively, these data indicate that blockade of Ser16-Hsp20 phosphorylation attenuates the cardioprotective effects of Hsp20 against ischemia/reperfusion injury, which may be attributable to suppressed autophagy and increased cell death. Therefore, phosphorylation of Hsp20 at serine 16 may represent a potential therapeutic target in ischemic heart disease.

  M. F Navedo , E. P Cheng , C Yuan , S Votaw , J. D Molkentin , J. D Scott and L. F. Santana

Rationale: L-Type (Cav1.2) Ca2+ channels are critical regulators of muscle and neural function. Although Cav1.2 channel activity varies regionally, little is known about the mechanisms underlying this heterogeneity.

Objective: To test the hypothesis that Cav1.2 channels can gate coordinately.

Methods and Results: We used optical and electrophysiological approaches to record Cav1.2 channel activity in cardiac, smooth muscle, and tsA-201 cells expressing Cav1.2 channels. Consistent with our hypothesis, we found that small clusters of Cav1.2 channels can open and close in tandem. Fluorescence resonance energy transfer and electrophysiological studies suggest that this coupling of Cav1.2 channels involves transient interactions between neighboring channels via their C termini. The frequency of coupled gating events increases in hypertensive smooth muscle and in cells expressing a mutant Cav1.2 channel that causes arrhythmias and autism in humans with Timothy syndrome (LQT8).

Conclusions: Coupled gating of Cav1.2 channels may represent a novel mechanism for the regulation of Ca2+ influx and excitability in neurons, cardiac, and arterial smooth muscle under physiological and pathological conditions.

  T. V Tkatchenko , R. A Moreno Rodriguez , S. J Conway , J. D Molkentin , R. R Markwald and A. V. Tkatchenko

The Postn gene encodes protein periostin. During embryonic development, it is highly expressed in the outflow tract (OFT) endocardial cushions of the developing heart, which give rise to several structures of the mature heart including the aortic valve. Periostin was previously implicated in osteoblast differentiation, cancer metastasis, and tooth and bone development, but its role in cardiac OFT development is unclear. To elucidate the role that periostin plays in the developing heart we analyzed cardiac OFT phenotype in mice after deletion of the Postn gene. We found that lack of periostin in the embryonic OFT leads to ectopic expression of the proosteogenic growth factor pleiotrophin (Ptn) and overexpression of delta-like 1 homolog (Dlk1), a negative regulator of Notch1, in the distal (prevalvular) cushions of the OFT. This resulted in suppression of Notch1 signaling, strong induction of the central transcriptional regulator of osteoblast cell fate Runx2, upregulation of osteopontin and osteocalcin expression, and subsequent calcification of the aortic valve. Our data suggest that periostin represses a default osteogenic program in the OFT cushion mesenchyme and promotes differentiation along a fibrogenic lineage. Lack of periostin causes derepression of the osteogenic potential of OFT mesenchymal cells, calcium deposition, and calcific aortic valve disease. These results establish periostin as a key regulator of OFT endocardial cushion mesenchymal cell fate during embryonic development.

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