1: Biochem Biophys Res Commun. 2005 Dec 16;338(2):1152-7. Epub 2005 Oct 21. 

Impairment of cardiomyogenesis in embryonic stem cells lacking scaffold protein
JSAP1.

Sato T, Hidaka K, Iwanaga A, Ito M, Asano M, Nakabeppu Y, Morisaki T, Yoshioka
K.

Division of Cell Cycle Regulation, Cancer Research Institute, Kanazawa
University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-0934, Japan.

We previously reported that c-Jun NH(2)-terminal kinase (JNK)/stress-activated
protein kinase-associated protein 1 (JSAP1), a scaffold protein for JNK
signaling, is important in embryonic stem (ES) cells during neurogenesis. In
that study, we also observed the altered expression of mesodermal marker genes,
which indicated that JSAP1 is involved in the differentiation of mesodermal
lineages. Here, we investigated the function of JSAP1 in cardiomyocyte
development using JSAP1-null ES cells, and found that cardiomyogenesis was
impaired in the JSAP1-null mutant. The JSAP1 deficiency resulted in lower gene
expression of the cardiac transcription factor Nkx2.5 and contractile proteins.
In contrast, the mutant showed a significantly higher expression of
mesoderm-related markers other than those of the cardiomyocyte lineage.
Together, these results suggest that JSAP1 may be important for the
differentiation of the mesodermal lineages, functioning as a positive factor for
cardiomyocyte differentiation, and as an inhibitory factor for differentiation
into other lineages.

PMID: 16253209 [PubMed - in process]


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2: Am J Physiol Heart Circ Physiol. 2000 Mar;278(3):H796-805. 

Altered molecular response to adrenoreceptor-induced cardiac hypertrophy in
Egr-1-deficient mice.

Saadane N, Alpert L, Chalifour LE.

Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General
Hospital, Montreal H3T 1E2, Quebec, Canada H3A 1A3.

Unmanipulated early growth response-1 (Egr-1)-deficient -/- mice have similar
heart-to-body weight ratios but express lower amounts of atrial natriuretic
factor (ANF), beta-myosin heavy chain (beta-MHC), skeletal actin, NGF1-A binding
protein (NAB)-2, Sp1, c-fos, c-jun, GATA-4, and Nkx2.5 than +/+ or +/- mice.
alpha-MHC, tubulin, and NAB-1 expression was similar. Isoproterenol (Iso) and
phenylephrine (PE) infusion into +/+ and -/- mice increased heart weight, ANF,
beta-MHC, skeletal actin, Sp1, NAB-2, c-fos, and c-jun expression, but induction
in -/- mice was lower. Only Iso + PE-treated +/+ mice showed induction of NAB-1,
GATA-4, and Nkx2.5. Foci of fibrosis were found in Iso + PE-treated -/- and +/+
mice. Surprisingly, vehicle-treated -/- mice displayed fibrosis and increased
Sp1, skeletal actin, Nkx2.5, and GATA-4 expression without hypertrophy. Minipump
removal caused the agonist-treated hearts and gene expression to regress to
control or near-control levels. Thus Egr-1 deficiency caused a blunted
catecholamine-induced hypertrophy response and increased sensitivity to stress.

PMID: 10710348 [PubMed - indexed for MEDLINE]


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3: Br J Pharmacol. 1999 Jul;127(5):1165-76. 

Expression of immediate early genes, GATA-4, and Nkx-2.5 in adrenergic-induced
cardiac hypertrophy and during regression in adult mice.

Saadane N, Alpert L, Chalifour LE.

Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General
Hospital, Montreal, Quebec, Canada.

Adrenoreceptor agonists induce a hypertrophic phenotype in vitro and in vivo. To
investigate the molecular remodeling in chronic cardiac hypertrophy we infused
adult male mice with vehicle. isoproterenol, phenylephrine or both agonists for
3, 7 or 14 days. All drugs increased cardiac mass. After minipump removal
cardiac mass regressed to control levels within 7 days after PE and ISO
treatment whereas ISO + PE treated hearts were incompletely regressed. ANF and
beta-MHC, but not alpha-MHC, expression were increased by agonists at all time
points. GATA-4, Nkx-2.5, Egr-1, c-jun and c-fos expression were increased after
3, 7 and 14 days of treatment. Expression was greatest after ISO+PE>
>ISO>PE>vehicle infusion suggesting a synergistic effect of adrenoreceptor
stimulation and indicating a greater effect of beta- than alpha-adrenergic
action in vivo. After PE or ISO drug withdrawal the HW/BW was normal and Egr-1,
c-jun, c-fos and GATA-4, but not Nkx2.5, expression dropped to control levels.
HW/BW regression was incomplete after ISO+PE and elevated levels of Egr-1, c-jun
and Nkx2.5 expression remained. A hydralazine-mediated reduction in blood
pressure had no effect on the agonist-induced cardiac hypertrophy or gene
expression. In conclusion, we found that continued agonist stimulation, and not
blood pressure. is responsible for the maintained increase in gene expression.
Further, we found the decrease in gene expression in the regression after drug
withdrawal was gene specific.

PMID: 10455263 [PubMed - indexed for MEDLINE]


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