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Mark Talan, M.D., Ph.D. Mark Talan, M.D., Ph.D., Senior Investigator
Chief, Translational Cardiovascular Studies Section
Laboratory of Cardiovascular Science

E-mail: talanm@grc.nia.nih.gov
Biography: Dr. Talan was trained as a physician at the First Leningrad Medical School in Russia. He received his Ph.D. in Physiology at the Pavlov Institute of Physiology in Russia where he continued to work as a principal researcher before coming to the NIA in 1980. His studies at the NIA in the area of thermoregulation, regulation of hemodynamics, and operant conditioning of autonomic functions evolved into his present interests of development and assessment of genetic therapeutic interventions in cardiovascular pathology using different experimental models.
Overview: Investigators in the section used constructs of endothelial growth factor (VEGF) with different vectors such as adenoviruses or plasmid/liposome complexes in experiments to deliver genes to promote angiogenesis. The major efforts are directed to characterize different experimental models of cardiac pathology in animals using the "cutting edge" in vivo technology such as pressure/volume analysis of cardiac function and Doppler echocardiography in mice. Great importance is assigned to the development of the optimal methods of delivery of appropriate genetic constructs to targeted tissue in vivo and to assess their therapeutic effectiveness. The Translational Cardiovascular Studies Section interacts with other LCS units/sections, serves as a resource for other GRC labs, and collaborates with industry and academic institutions in animal trials that employ gene targeted therapy.
I. Therapeutic Angiogenesis: The broad objective of this program is to perform preclinical experimentation on animal models of myocardial and hindlimb ischemia as well as on different experimental models of heart failure to evaluate the therapeutic potential of gene therapy with angiogenic growth factors. In vivo experiments are aimed at characterizing clinically relevant animal models and optimal conditions, vectors, and routes of delivery at which gene transfer of angiogenic growth factors induce therapeutic angiogenesis.
A) Adenovirus-mediated Gene Transfer of VEGF121 Stimulates Angiogenesis in Normoperfused Skeletal Muscles: Administration of angiogenic factors has been shown to induce angiogenesis in the presence of tissue ischemia and to improve blood perfusion. However, there were no clear evidence that angiogenesis can be induced in normoperfused skeletal muscles. Furthermore, it is also unclear if once induced, the new-formed vessels can preserve blood perfusion upon induction of ischemia. Accordingly, we tested the hypothesis that adenovirus-mediated intramuscular (IM) gene therapy with vascular endothelial growth factor (AdCMV.VEGF121) could augment collateral vessel development in nonischemic skeletal muscles and, subsequently, attenuate the hemodynamic deficits related to induced ischemia. Animals received IM injections of AdCMV.VEGF121, AdCMV.Null, or saline in the thigh 4 weeks (rabbits) or 2 weeks (rats) before induction of ischemia in the injected limb. In rabbits, increased tissue perfusion (TP) to the ischemic limb was documented by a superior calf blood pressure ratio for VEGF121 group versus controls, improved blood flow in the ischemic gastrocnemius (P<.001) and more angiographically recognizable collateral vessels (angioscore) (P<.0001), at day 1 after surgery. In rats, we found a 29% increase in capillary density for VEGF121 (P<.03 vs. saline) and an improvement of the bioenergetic profile of the gastrocnemius muscle obtained through 31P NMR spectroscopy. We concluded that IM administration of VEGF121 induces angiogenesis in normoperfused skeletal muscles and the newly formed vessels preserve blood perfusion once ischemia develops. This prophylactic approach could have therapeutic significance as part of an alternative treatment strategy for patients with peripheral vascular disease.
B) Treatment with VEGF165 Encoded in Plasmid/liposome Complex Stimulates Angiogenesis in Rabbits Hindlimb Ischemia Model: Liposome-based vectors for gene therapy are considered to have lower transfection rate that adenovirus-based vectors. Nevertheless, comprehensive, in vivo, efficacy evaluation of liposome-based endothelial growth factors gene transfer for the treatment of tissue ischemia was not previously conducted. Two days after surgical removal of the femoral artery on one side, the ischemic tissue of different groups of rabbits was injected with different concentrations of plasmid/liposome construct encoded with VEGF165, control substance (plasmid/liposome without expression cassette), or saline. Blood pressure distally to removed femoral artery, tissue blood flow, postmortem angiography and capillary density were assessed weekly, for four weeks. Accelerated development of new capillaries and larger vessels was confirmed by all assessment techniques during the first two weeks in VEGF165 treated groups. In vivo angiogenic efficacy of plasmid/liposome vector encoded with VEGF165 was not inferior to that of adenoviral vector.
II. Experimental Model of Post Myocardial Infarction Chronic Heart Failure: In keeping with a broad objective of the program, we mustered the techniques for in vivo assessment of cardiac function in rats and mice - the high resolution Doppler-Echocardiography and pressure/volume loop analysis with intracardiac pressure-conductance catheter. Using this "cutting edge" technology, we are conducting extensive functional and dynamic characterization of chronic heart failure which is developing subsequently to ligation of a coronary artery in mice and rats. This experimental model will be used for transgenic-based studies of the role of different receptors pathways in development of heart failure as well as for development of gene and other therapeutic modalities based treatment of chronic heart failure.
The experimental model of coronary ligation in rats expressed all facets of early and late, structural and functional remodeling described in the literature: increase of earlier and later apoptosis, dilatation of the ventricular chamber, compensatory myocyte hypertrophy, reduction of systolic function, myocardial stiffness, and diastolic dysfunction. For instance, early remodeling was characterized by the fall of ejection fraction (EF) from 60% to less than 40% (echocardiography), and, 24 hrs after coronary ligation, the 35% of cardiomyocyte nuclei across the area at risk were stained positively for apoptosis. During the next seven weeks the EF fell further, by 15% comparing with the value at week 1, and 3 times more of cardiomyocyte nuclei succumbed to apoptosis than in sham operated hearts. The most interesting functional characteristics of late remodeling were shown through pressure-volume analyses of left ventricular performance. Traditional index of systolic function, dP/dt showed a significant, 45% decline in coronary ligated rats. The more sophisticated, load-independent index of systolic performance, Preload Recruitable Stroke Work showed even larger, more than 50% decline. The end-diastolic stiffness, Eed, doubled in MI rats indicating a diastolic dysfunction. The Ees, end-systolic elastance, one of components of myocardial contractility significantly fell in MI rats, while arterial elastance, the measure of after-load, increased, reflecting the very unfavorable relation (uncoupling) between LV and vascular system from the perspective of energy transfer - Ea/Ees ratio more than doubled in MI animals, i.e., weakened LV was pumping blood against increased vascular load.
Similar characteristics of left ventricular remodeling had been shown in the mice model of coronary ligation. Moreover, in mice we not only mustered the technique for reliable induction of large myocardial infarctions by ligation of main left descending coronary artery, we delineated a technique for blind ligation of small left ventricular branches which reliably induced small, but transmural MI of predictable location and uniform size.
III. Translational Studies, Targeting Early and Late Left Ventricular Remodeling:
A) Targeting Early Remodeling: Erythropoietin Reduces Myocardial Infarction and Left Ventricular Functional Decline Following Coronary Artery Ligation in Rats: Erythropoietin (EPO), natural stimulant of erythropoiesis, recently emerged as potential antiapoptotic factor. We tested the hypothesis that single treatment with EPO will reduce the cardiac damage induced by coronary ligation and subsequent decline of cardiac function. In experiments in rats, we showed that single intraperitoneal injection of recombinant human EPO (3000 IU/kg) immediately after ligation of the coronary artery, results in 75% reduction of the size of myocardial infarction eight weeks later. During eight weeks after induction of myocardial infarction, left ventricular remodeling and function decline in EPO treated rats were significantly attenuated and statistically not different from that in sham operated animals. Twenty-four hours after ligation of coronary artery, the amount of apoptotic myocytes measured in the myocardial risk area (area immediately adjacent to the infarct site) was reduced in half in the EPO treated rats in comparison to untreated animals. Further experiment established that the effective EPO dose can be reduced to 500 IU/kg, i.e. in the range of FDA doses approved for the treatment of anemia.
B) Targeting Late Remodeling: Effects of Chronic Pharmacological Manipulations of b-Adrenergic Receptor Subtypes Signaling in an Experimental Model of Dilated Ischemic Cardiomyopathy in Rats: The role of b-adrenerging receptors (AR) subtype signaling in development of CHF is clearly important but purely understood. It is widely accepted now that b-1 AR activation is associated with development of CHF, thus, the use of b-1 AR antagonists became a recommended therapy for HF. The possible role of b-2 AR agonists remains debatable, however the consensus is that similarly to b-1 AR, activation of b-2 AR during CHF is harmful. Recent research in LCS using single myocytes indicated that b-2 AR agonist, fenoterol, possesses a unique ability to activate Gs, but not Gi pathways. Capitalizing on this finding, we studied the effects of chronic treatment with b-2 AR agonist, fenoterol, and b-1 AR blocker, metaprolol, in rats starting 2 weeks after ligation of a coronary artery. Our results indicated that both, b-2 AR agonist and b-1 AR blocker reduced the apoptosis in myocardium and attenuated the development of CHF, i.e. left ventricular remodeling and functional decline. However, they affected different aspects of cardiac function: metaprolol improved systolic cardiac performance by increasing left ventricular elastance, while fenoterol achieved the same result by reducing the arterial elastance (after-load). Metaprolol did not improve diastolic function, while fenoterol normalized it. Only fenoterol treatment arrested the infarct expansion, resulting in actual decrease of the infarct relative size. Our results suggest that beneficial effects of chronic treatment with b-2 AR agonists and b-1 AR blockers in CHF might be complimentary.
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Updated: Friday November 09, 2007