The research in our laboratory is focused on investigation of the molecular mechanisms underlying heart development and disease. We have identified two novel transcription factors that appear to play a critical role in myogenic development. One transcription factor CLP-1 (Cardiac Lineage Associated Protein), is expressed very early i. e., prior to cardiac fate assignment, in development. The pattern of CLP-1 expression based on whole mount in situ hybridization coincides remarkably well with the established morphogenetic field of early heart formation. Treatment of chicken blastoderm with antisense CLP-1 oligonucleotides resulted in an apparent cardiac bifida condition and abnormal bulbous heart morphology. At the molecular level, the expression of the downstream well documented cardiac specific markers, such as, cNKX2.5 and GATA 4, was ablated, suggesting that CLP-1 may be an important upstream regulator of these proteins in the genetic program underlying cardiogenesis.
In addition to development, our laboratory is interested in signal transduction mechanisms that are active in the pathological states of heart development, such as, hypertrophy and ischemia. We have recently demonstrated that angiotensin II (Ang II) activates the Jak/STAT pathway resulting in enhanced binding of STAT-3, STAT-5A and STAT-6 to the angiotensinogen (ANG) promoter which causes the induction of the autocrine loop of renin-angiotensin system (RAS) during development of myocardial hypertrophy. Nuclear extract isolated from the adult hypertrophic SHR hearts showed a consistent high level of activated STAT proteins whereas those from STAT 6 null (-/-) mutant mice have a significant reduced level of activated STATs. Our follow-up studies with isolated and perfused rat heart subjected to ischemic stress also showed an induction of the Jak/STAT pathway and the consequent activation of the RAS components assayed by STATs/binding to the target site DNA. Pre-conditioning of the heart to ischemic stress produced a substantial reduction in STAT/DNA binding. Taken together, it appears that signaling rendered by the Jak/STAT pathway constitutes an essential step in modulation of the transcriptional machinery essential for development of various pathologies associated with angiotensin II.
Funded by multiple grants from the National Institute of Health.
RECENT PUBLICATIONS
1. Mascareno, E., Dhar, M., and Siddiqui, M.A.Q. STAT Protein Dependent Activation of Angiotensinogen Promoter: A cellular Signal for Hypertrophy in Cardiac Muscle. Proc. Nat'l. Acad. Sci., U.S.A. 95, 5590-5594, 1998.
2. Ghatpande, S., Goswami, S., Shafiq, S., Rong, G., and Siddiqui, M.A.Q. Identification of a Novel Cardiac Lineage Associated Protein (CLP-1); A Candidate Regulator of Cardiogenesis. Develop. Biol. 208, 210-220, 1999.
3. Ghatpande, S., Goswami, S., Mascareno, E., and Siddiqui, M.A. Q. Signal Transduction Adaptation in Embryonic Heart Development and during Myocardial Hypertrophy. Mol. Cell Cardiol. 196, 93-97, 1999.
4. Wagner, M., Mascareno, E., and Siddiqui, M.A.Q. Cardiac Hypertrophy: Signal Transduction, Transcriptional Adaptation and Altered Growth Control. N.Y. Acad. Sci. U.S.A. 874, 1-10, 1999.
5. Zaugg, M., Xu, W., Lucchinetti, E., Shafiq, S., Jamali, N., and Siddiqui, M.A.Q. b-Adrenergic Receptor Sub-Types Differentially Affect Apoptosis in Adult Rat Ventricular Myocytes. Circulation 102, 344-350, 2000.
M.A.Q. SIDDIQUI, PH.D.
Professor and Chairman
Department of Anatomy and Cell Biology, Box 5
Phone: 270-1014, Fax: 270-3732
e-mail: msiddiqui@netmail.hscbklyn.edu
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