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Articles by J. D. Molkentin
Total Records ( 4 ) for J. D. Molkentin
  Q Liu , X Chen , S. M MacDonnell , E. G Kranias , J. N Lorenz , M Leitges , S. R Houser and J. D. Molkentin

Protein kinase (PK)C, PKCβ, and PKC comprise the conventional PKC isoform subfamily, which is thought to regulate cardiac disease responsiveness. Indeed, mice lacking the gene for PKC show enhanced cardiac contractility and reduced susceptibility to heart failure. Recent data also suggest that inhibition of conventional PKC isoforms with Ro-32-0432 or Ro-31-8220 enhances heart function and antagonizes failure, although the isoform responsible for these effects is unknown. Here, we investigated mice lacking PKC, PKCβ, and PKC for effects on cardiac contractility and heart failure susceptibility. PKC–/– mice, but not PKCβ–/– mice, showed increased cardiac contractility, myocyte cellular contractility, Ca2+ transients, and sarcoplasmic reticulum Ca2+ load. PKC–/– mice were less susceptible to heart failure following long-term pressure-overload stimulation or 4 weeks after myocardial infarction injury, whereas PKCβ–/– mice showed more severe failure. Infusion of ruboxistaurin (LY333531), an orally available PKC/β/ inhibitor, increased cardiac contractility in wild-type and PKCβ–/– mice, but not in PKC–/– mice. More importantly, ruboxistaurin prevented death in wild-type mice throughout 10 weeks of pressure-overload stimulation, reduced ventricular dilation, enhanced ventricular performance, reduced fibrosis, and reduced pulmonary edema comparable to or better than metoprolol treatment. Ruboxistaurin was also administered to PKCβ–/– mice subjected to pressure overload, resulting in less death and heart failure, implicating PKC as the primary target of this drug in mitigating heart disease. As an aside, PKCβ triple-null mice showed no defect in cardiac hypertrophy following pressure-overload stimulation. In conclusion, PKC functions distinctly from PKCβ and PKC in regulating cardiac contractility and heart failure, and broad-acting PKC inhibitors such as ruboxistaurin could represent a novel therapeutic approach in treating human heart failure.

  Q Liu , M. A Sargent , A. J York and J. D. Molkentin

Rationale: Apoptosis signal-regulating kinase (ASK)1 is a central upstream kinase in the greater mitogen-activated protein kinase cascade that mediates growth and death decisions in cardiac myocytes in response to diverse pathological stimuli.

Objective: However, the role that ASK1 plays in regulating the cardiac hypertrophic response in vivo remains controversial.

Methods and Results: Here, we generated mice with cardiac-specific and inducible overexpression of ASK1 in the heart to assess its gain-of-function effect. ASK1 transgenic mice exhibited no induction of cardiac hypertrophy or pathology at 3 and 12 months of age, and these mice showed an identical hypertrophic response to controls following 2 weeks of pressure-overload stimulation or isoproterenol infusion. Although ASK1 overexpression did not alter the cardiac hypertrophic response, it promoted cardiomyopathy and greater TUNEL following pressure-overload stimulation and myocardial infarction. Indeed, ASK1 transgenic mice showed a greater than 2-fold increase in ischemia reperfusion-induced injury to the heart compared with controls. Examination of downstream signaling showed a prominent activation of mitogen-activated protein kinase kinase 4/6 and c-Jun NH2-terminal kinase (JNK)1/2 (but not p38 or extracellular signal-regulated kinases [ERKs]), inhibition of calcineurin-NFAT (nuclear factor of activated T cells), and induction of Bax in the hearts of ASK1 transgenic mice following 1 and 8 weeks of pressure-overload stimulation. Mechanistically, cardiomyopathy associated with ASK1 overexpression after 8 weeks of pressure overload was significantly reduced in the calcineurin Aβ–null (CnAβ–/–) background.

Conclusions: These results indicate that ASK1 does not directly regulate the cardiac hypertrophic response in vivo, but it does alter cell death and propensity to cardiomyopathy, in part, through a calcineurin-dependent mechanism.

  J. H van Berlo , J. W Elrod , M. M. G van den Hoogenhof , A. J York , B. J Aronow , S. A Duncan and J. D. Molkentin

The transcriptional code that programs maladaptive cardiac hypertrophy involves the zinc finger–containing DNA binding factor GATA-4. The highly related transcription factor GATA-6 is also expressed in the adult heart, although its role in controlling the hypertrophic program is unknown.


To determine the role of GATA-6 in cardiac hypertrophy and homeostasis.

Methods and Results:

Here, we performed a cardiomyocyte-specific conditional gene targeting approach for Gata6, as well as a transgenic approach to overexpress GATA-6 in the mouse heart. Deletion of Gata6-loxP with Nkx2.5-cre produced late embryonic lethality with heart defects, whereas deletion with β-myosin heavy chain-cre (βMHC-cre) produced viable adults with >95% loss of GATA-6 protein in the heart. These latter mice were subjected to pressure overload–induced hypertrophy for 2 and 6 weeks, which showed a significant reduction in cardiac hypertrophy similar to that observed Gata4 heart-specific deleted mice. Gata6-deleted mice subjected to pressure overload also developed heart failure, whereas control mice maintained proper cardiac function. Gata6-deleted mice also developed less cardiac hypertrophy following 2 weeks of angiotensin II/phenylephrine infusion. Controlled GATA-6 overexpression in the heart induced hypertrophy with aging and predisposed to greater hypertrophy with pressure overload stimulation. Combinatorial deletion of Gata4 and Gata6 from the adult heart resulted in dilated cardiomyopathy and lethality by 16 weeks of age. Mechanistically, deletion of Gata6 from the heart resulted in fundamental changes in the levels of key regulatory genes and myocyte differentiation–specific genes.


These results indicate that GATA-6 is both necessary and sufficient for regulating the cardiac hypertrophic response and differentiated gene expression, both alone and in coordination with GATA-4.

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