Polly Hofmann, Ph.D.
1982 B.S. University of Illinois, Champaign, IL
1987 Ph.D., University of Pittsburgh, School of Medicine
On a beat-to-beat basis, force and rate of cardiac contractions can be modified through kinase-dependent phosphorylations and phosphatase-dependent dephosphorylations of myocardial proteins. Short and long-term modification of various myocardial proteins by phosphorylation plays an important role in cardiac survival following ischemia and myocardial function of the hypertrophied heart. In our lab we specifically focus on the molecular mechanisms by which ser/thr phosphatases, such as PP1 and PP2a, are modified and the role of phosphatases in altering myocardial function and survival. Identification of these mechanisms of action under physiologic and pathologic conditions is key to the design of effective clinical therapies.
Current Techniques Utilized:
- enzymatic isolation of ventricular myocytes
- determination of single cardiac myocyte mechanical properties:
- velocity of unloaded shortening
- isometric tension generation as a function of [Ca2+]
- rate of relaxation
- Western analysis to determine protein expression and phosphorylation state
- immunoprecipitation to determine second messenger binding partners
- biochemical assays to measure activity of second messengers
- 32P-autoradiographic analysis of myocardial proteins to determine protein target(s) of second messenger activation
- confocal laser microscopy for visualization of second messenger location in cardiomyocytes
- determination of Ca2+ activated actin-myosin ATPase
- determination of whole heart function, before and after an ischemic challenge, in wild type or genetically altered hearts
- HPLC analysis of adenine nucleotides and high energy phosphates
- si RNA in cultured cardiomyocytes
American Heart Association, Grant-In-Aid, " Protein Phosphatase 2a in the Heart", Polly A Hofmann, Ph.D., PI, 2006 - 2008
National Institutes of Health K08, "Ischemia Reperfusion in the A2A and A2B Knockout Hearts", R Ray Morrison, M.D., P.I.., Polly A. Hofmann, Ph.D. Sponsor 2003-2008
National Institutes of Health R15, "Water-Soluble and Metabolically Stable Calpain Inhibitors as Cardioprotectants", Isaac Donkor, Ph.D., P.I.., Polly A Hofmann, Ph.D., Co-Investigator. 2006-2008
Liu, Q. and P.A. Hofmann. Modulation of protein phosphatase 2a by adenosine A1 receptors in cardiomyocytes: role for p38 MAPK.. American Journal of Physiology, 285:H97-103, 2003.
Pyle, W.G. and P.A. Hofmann. Protein kinase C mediates k-opioid receptor - dependent cardioprotection. American Journal of Physiology, 285:H1220-8, 2003.
E.M. Grey, C. Chan, Y. Chen and P.A. Hofmann. Age-related functional effects linked to phosphatase activity in ventricular myocytes. American Journal of Physiology, 285:H90-96., 2003.
Chen, Y., R. Rajashree, Q. Liu and P.A. Hofmann. Arsenite-induced p38 MAPK and PKC activation alters contractile properties of cardiac myocytes. American Journal of Physiology, 285:H2578-86, 2003.
Liu, Q.L. and P.A. Hofmann. Protein phosphatase 2A-mediated cross-talk between p38 MAPK and ERK in apoptosis of cardiac myocytes. American Journal of Physiology, 286:H2204-12, 2004.
Rajashree, R., B.C. Blunt, and P.A. Hofmann. Modulation of myosin phosphatase targeting subunit and protein phosphatase 1 in the heart. American Journal of Physiology, 289:H1736-43, 2005.
Blunt, B.C., Y. Chen, J.D.Potter, P.A. Hofmann. Modest actomyosin energy conservation increases myocardial postischemic function. American Journal of Physiology, 288:H1088-96 2005.
Deshmukh, P.D., B.C. Blunt and P.A. Hofmann. Acute modulation of PP2a and troponin I phosphorylation in ventricular myocytes: studies with a novel PP2a peptide inhibitor. American Journal of Physiology, 292(2):H792-9, 2007.
Zhu, Z., P. Hofmann and J.K. Buolamwini. Cardioprotective effects of novel tetrahydroisoquinoline analogues of nitrobenzymercaptopurine riboside in perfuse isolated hearts. American Journal of Physiology, 292(6):H2921-6, 2007.
Blunt, B.C., Creek A.T., Henderson D.C., and P.A. Hofmann. H2O2 activation of HSP25/27 protects desmin from calpain proteolysis in rat ventricular myocytes. American Journal of Physiology, 293(3):H1518-25, 2007.
Morrison, R.R., X. Tan, C. Ledent, S.J Mustafa and P.A. Hofmann. Targeted deletion of A2A adenosine receptors attenuates the protective effects of myocardial postconditioning. American Journal of Physiology, 293(4):H2523-9, 2007.
Hofmann, P.A., M. Israel, Y. Koseki, J.J. Jenkins, M. Arsura, A. Janik, T.W. Sweatman, L. Lothstein. N-Benzyladriamycin-14-valerate (AD 198): a non-cardiotoxic anthracycline that is cardioprotective through PKC activation. Journal of Pharmacology and Experimental Therapeutics, 323(2):658-64, 2007.
Leary PJ, Rajasekaran S, Morrison RR, Tuomanen EI, Chin TK, and PA Hofmann. A cardioprotective role for platelet-activating factor through NOS-dependent S-nitrosylation. American Journal of Physiology. 294(6):H2775-84, 2008.