The Parmacek laboratory has a longstanding interest in examining the molecular programs that regulate vascular smooth muscle cell and cardiac myocyte development and differentiation. Dr. Parmacek cloned and characterized members of the GATA-4/5/6 family of zinc finger transcription factors and used gene targeting techniques in mice to elucidate the distinct functions of GATA-4 and GATA-6 in the cardiovascular system. The Parmacek laboratory also used transgenic techniques to show that an SRF-dependent transcriptional program regulates vascular SMC differentiation.
More recently, the Parmacek Lab reported that myocardin is a critical SRF cofactor that regulates vascular smooth muscle cell differentiation and modulation of smooth muscle cell phenotype. These studies are relevant to understanding the molecular basis of angiogenesis and the pathophysiology of vascular proliferative syndromes including atherosclerosis.
In collaboration with other Penn cardiologists, Dr. Parmacek performs translational research studies focusing on stem cells and other novel agents that may be used to treat cardiovascular disease.
The Parmacek laboratory examines the molecular mechanisms underlying cardiovascular development with particular focus on elucidating the transcriptional programs controlling differentiation and phenotypic modulation of muscle cell lineages. These studies are fundamentally important at a basic level and have provided important insights into the pathogenesis of atherosclerosis, congenital heart disease and cardiac hypertrophy.
Myocardin Function in the Embryonic and Adult Heart
The Parmacek Laboratory and Penn Molecular Cardiology Center routinely apply gene targeting in embryonic stem cells and mice to examine the molecular basis of cardiovascular development and adaptation.
Myocardin-Related Transcription Factor (MRTF) Function in the Vasculature
The Parmacek laboratory has elucidated the transcriptional programs and signaling mechanisms that control vascular smooth muscle cell development and differentiation. Members of the Parmacek laboratory generated transgenic mice that revealed the critical role that the MADS box transcription factor SRF plays in regulation of contractile smooth muscle cell gene expression. More recently, Lab members demonstrated that myocardin and the two myocardin related transcription factors (MRTFs)-A and -B act as critical SRF coactivators transducing signals from the SMC cytoskeleton and modulating vascular smooth muscle cell phenotype in response to injury.
In situ hybridization analyses demonstrating myocardin mRNA (pink signal) in the normal mouse heart.
Heart harvested from P300 MyHC-Cre/MyocdF/F-mutant mouse.
Electron microscopy of MyocdF/F mouse heart demonstrating myofibrillar striations.
MKL1/2 Function in Embryonic Stem Cells
The Parmacek Lab is investigating the role of MRTF-A (MKL1/MAL) and MRTF-B (MKL2), two members of the myocardin protein family that have been characterized as mechanical stress-induced coactivators that promote the activation of transcription of smooth muscle cytoskeletal proteins.
Mice harboring loss-of-function mutations in myocardin, MRTF-A, and MRTF-B, respectively, display distinct phenotypes, including cell autonomous defects in vascular smooth muscle cell and myoepithelial cell differentiation and function.
Notch signaling and cardiovascular development
The Parmacek laboratory reported that activation of Notch signaling mediated through members of the HRT family of basic helix-loop-helix transcription factors represses smooth muscle cell (SMC) differentiation and expression of genes encoding smooth muscle cell contractile markers. Notch signaling is an essential factor in vascular patterning and response of the vasculature to injury and growth factor stimulation.
GATA4/5/6 signaling in the heart and vascular system
Members of the Parmacek laboratory characterized the GATA-4/5/6 subfamily of zinc finger transcription factors that play critical roles in the developing heart and vascular system. Gene targeting experiments in ES cells and mice revealed the critical role that GATA4 and GATA6 play in cardiovascular and pulmonary development.
In collaboration with other members of Division of Cardiovascular Medicine at the University of Pennsylvania, Dr. Parmacek has initiated a translational research program for metabolic vascular disease.
Confocal microscopy reveals loss of myofibrils in Ad-Cre-transduced cells including loss of α-cardiac actin (green stain).
Cardiac outflow tract of E14.5 wild-type embryo.
- Jianhe Huang, MD, PhD
- Jian Li, MD
- Nina Bowens, MD
- Xiaohong Zhu, MD
The Parmacek Lab publishes clinical reports in top-ranked medical journals that reflect the depth and breadth of its research program.
- Huang J, Elicker J, Bowens N, Liu X, Chen L, Cappola TP, Zhu X, Parmacek MS. Myocardin regulates BMP10 expression and is required for heart development. J Clin Invest. 2012;122(10):3678-91
- Li J, Bowens N, Cheng L, Zhu Z, Chen M, Hannenhalli S, Cappola TP, Parmacek MS. Myocardin-like protein 2 regulates TGFβ signaling in embryonic stem cells and the developing vasculature. Development 2012;139(19):3531-42
- Rong L, Liu J, Qi Y, Graham AM, Parmacek MS, Li S. GATA6 promotes cell survival by upregulating BMP-2 expression during embryonic stem cell differentiation. Mol Biol Cell. 2012;23(18):3754-63
- Rader DJ, Parmacek MS. Secreted miRNAs regulate atherogenesis. Nat Cell Biol. 2012;14:233-235.
- Shen D, Li J, Lepore JJ, Anderson TJT, Sinha S, Yin AY, Cheng L, Dedhar S, Parmacek MS,* Gerszten RE.* Aortic aneurysm generation in mice with targeted deletion of integrin linked kinase (ILK) in vascular smooth muscle cells. Circ Res. 2011;109:616-628.
- Beppu H, Malhotra R, Beppu Y, Lepore JJ, Parmacek MS, Bloch KD. BMP type II receptor regulates positioning of outflow tract and remodeling of atrioventricular cushion during cardiogenesis. Dev Biol. 2009;331:167-175. PMCID: PMC2745439
- Cardiomyocyte renewal. N Engl J Med. 2009;361:86-88.
- Huang J, Lu MM, Cheng L, Yuan LJ, Zhu X, Stout AL, Chen M, Li J, Parmacek MS. Myocardin is required for cardiomyocyte survival and maintenance of heart function. Proc Natl Acad Sci USA. 2009;106:18734-18739. PMCID: PMC2773995
- Zhang Z, Goss AM, Cohen ED, Kadzik R, Lepore JJ, Muthukumaraswamy K, Yang J, DeMayo F, Whitsett JA, Parmacek MS, Morrisey EE. A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration. Nat Genet. 2008; 40:862-870. PMCID: PMC2562713
- Huang J, Cheng L, Li J, Chen M, Zhou D, Lu MM, Proweller A, Epstein JA, Parmacek MS. Myocardin regulates smooth muscle cell contractile genes required for closure of the ductus arteriosus. J Clin Invest. 2008;118:515-525.
- Proweller A, Wright AC, Horng D, Cheng L, Lu MM, Lepore JJ, Pear WS, Parmacek MS. Notch signaling in vascular smooth muscle cells is required to pattern the cerebral vasculature. Proc Natl Acad Sci USA. 2007;104:16275-16280.
- Lepore JJ, Mericko PA, Cheng L, Lu MM, Morrisey EE, Parmacek MS. GATA-6 regulates semaphorin 3C and is required in cardiac neural crest for cardiovascular morphogenesis. J Clin Invest. 2006;116:929-939.
- Li J, Zhu X, Chen M, Cheng L, Zhou D, Lu MM, Du K, Epstein JA, Parmacek MS. Myocardin-related transcription factor B is required in cardiac neural crest for smooth muscle differentiation and cardiovascular development. Proc Natl Acad Sci USA. 2005;102:8916-8921.