Drug discovery and cell therapy in cardiovascular diseases

Contacts


 

PROJECT RESEARCH

 

Dr. Motterlini’s laboratory has a long-standing interest in the biological significance of heme oxygenase-1 (HO-1), a ubiquitous defensive protein that degrades heme to carbon monoxide (CO), biliverdin and bilirubin (see Figure 1) [1].

 

Together with Dr. Roberta Foresti, their team has extensively contributed to understand how HO-1 and endogenous bilirubin and CO render vascular and cardiac tissues more resistant to oxidative stress and injury [2-7].

 

Within the frame of our research strategies, we have also worked extensively on the identification of small molecules that specifically target the HO-1/CO pathway for the implementation of new pharmacological approaches to treat cardiac disorders and inflammation.

 

Notably, this work led to the pioneering discovery and characterization of CO-releasing molecules (CO-RMs), compounds that deliver controlled amounts of CO to tissues (see Figure 2) [8-10].

 

 

 

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Several studies by our group, which have been corroborated by other laboratories, have confirmed that CO-RMs are pharmacologically active by exerting vasodilatory, anti-ischemic, anti-inflammatory and bactericidal effects in vitro and in animal models of disease [11-17].

 

As the intracellular target(s) of CO remains elusive, part of our research plan is now to investigate the mechanism of action of CO with particular emphasis on the effect of CO-RMs on redox signaling and mitochondrial bioenergetics [18].

 

In parallel, we are also working on the design and synthesis of effective small molecules that induce HO-1 by targeting the transcription factor Nrf2 which controls HO-1 gene expression (see Figure 2). This is based on our original findings that curcumin and other natural compounds strongly induce HO-1 protein expression and activity via transcriptional regulation of Nrf2 [19-25].

 

The recent synthesis of “HYCOs”, novel hybrid molecules able to activate the Nrf2/HO-1 axis and simultaneously release CO, is an example of our drug discovery approach [26]. As part of these projects, which are conducted in collaboration with a chemistry group (Dr. Michael Rivard), the team aims to investigate in depth the mechanism(s) of action by which HO-1 and CO exert its pharmacological effects by modulating mitochondrial function, metabolism and inflammation.

 

Complementary to our drug discovery approach, the team relies on the expertise of Dr. Anne Marie Rodriguez in stem cell therapy for cardiac and tissue regeneration. Dr. Rodriguez contributed over the years to understand how stem cells exert their protective effects on injured cardiomyocytes. Her studies showed that communication between mesenchymal stem cells (MSC) and suffering cardiomyocytes via formation of nanotubules is crucial for promoting the activation of cardioprotective factors secreted by MSC, leading to an increase in their angiogenic and chemoattractant functions and consequently aiding the regenerative process [27; 28]. Dr. Rodriguez is investigating protective pathways in the repairing and rejuvenating capacities of stem cells, with particular emphasis on HO-1/CO as a therapeutic target.

 

The team is also investigating approaches that combine the use of CO-RMs and HYCOs with stem cell technologies (see Figure 2).

 

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References

 

  1. Motterlini R. & Foresti R. Heme oxygenase-1 as a target for drug discovery. Antioxid. Redox. Signal. 20, 1810-1826 (2014).
  2. Foresti R., Clark J. E., Green C. J. & Motterlini R. Thiol compounds interact with nitric oxide in regulating heme oxygenase-1 induction in endothelial cells. Involvement of superoxide and peroxynitrite anions. J. Biol. Chem. 272, 18411-18417 (1997).
  3. Foresti R., Green C. J., Clark J. E. & Motterlini R. Peroxynitrite induces heme oxygenase-1 in vascular endothelial cells. J. Physiol. 506, 36-37 (1998).
  4. Motterlini R., Gonzales A., Foresti R., Clark J. E., Green C. J. & Winslow R. M. Heme oxygenase-1-derived carbon monoxide contributes to the suppression of acute hypertensive responses in vivo. Circ. Res. 83, 568-577 (1998).
  5. Clark J. E., Foresti R., Sarathchandra P., Kaur H., Green C. J. & Motterlini R. Heme oxygenase-1-derived bilirubin ameliorates post-ischemic myocardial dysfunction. Am. J. Physiol. Heart Circ. Physiol. 278, H643-H651 (2000).
  6. Foresti R. & Motterlini R. The heme oxygenase pathway and its interaction with nitric oxide in the control of cellular homeostasis. Free Rad. Res. 31, 459-475 (1999).
  7. Clark J. E., Foresti R., Green C. J. & Motterlini R. Dynamics of haem oxygenase-1 expression and bilirubin production in cellular protection against oxidative stress. Biochem. J. 348, 615-619 (2000).
  8. Motterlini R., Clark J. E., Foresti R., Sarathchandra P., Mann B. E. & Green C. J. Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities. Circ. Res. 90, e17-e24 (2002).
  9. Johnson T. R., Mann B. E., Clark J. E., Foresti R., Green C. J. & Motterlini R. Metal carbonyls: a new class of pharmaceuticals? Angew. Chem. Int. Ed. Engl. 42, 3722-3729 (2003).
  10. Motterlini R., Sawle P., Bains S., Hammad J., Alberto R., Foresti R. & Green C. J. CORM-A1: a new pharmacologically active carbon monoxide-releasing molecule. FASEB J. 19, 284-286 (2005).
  11. Foresti R., Hammad J., Clark J. E., Johnson R. A., Mann B. E., Friebe A., Green C. J. & Motterlini R. Vasoactive properties of CORM-3, a novel water-soluble carbon monoxide-releasing molecule. Br. J. Pharmacol. 142, 453-460 (2004).
  12. Clark J. E., Naughton P., Shurey S., Green C. J., Johnson T. R., Mann B. E., Foresti R. & Motterlini R. Cardioprotective actions by a water-soluble carbon monoxide-releasing molecule. Circ. Res. 93, e2-e8 (2003).
  13. Sawle P., Foresti R., Mann B. E., Johnson T. R., Green C. J. & Motterlini R. Carbon monoxide-releasing molecules (CO-RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW264.7 murine macrophages. Br. J. Pharmacol. 145, 800-810 (2005).
  14. Sandouka A., Fuller B. J., Mann B. E., Green C. J., Foresti R. & Motterlini R. Treatment with carbon monoxide-releasing molecules (CO-RMs) during cold storage improves renal function at reperfusion. Kidney Int. 69, 239-247 (2006).
  15. Yabluchanskiy A., Sawle P., Homer-Vanniasinkam S., Green C. J., Foresti R. & Motterlini R. CORM-3, a carbon monoxide-releasing molecule, alters the inflammatory response and reduces brain damage in a rat model of hemorrhagic stroke. Crit Care Med. 40, 544-552 (2012).
  16. Desmard M., Foresti R., Morin D., Dagoussat M., Berdeaux A., Denamur E., Crook S. H., Mann B. E., Scapens D., Montravers P., Boczkowski J. & Motterlini R. Differential Antibacterial Activity Against Pseudomonas aeruginosa by Carbon Monoxide-Releasing Molecules. Antioxid. Redox. Signal. 16, 153-163 (2012).
  17. Motterlini R. & Otterbein L. E. The therapeutic potential of carbon monoxide. Nat. Rev. Drug Discov. 9, 728-743 (2010).
  18. Kaczara P., Motterlini R., Rosen G. M., Augustynek B., Bednarczyk P., Szewczyk A., Foresti R. & Chlopicki S. Carbon monoxide released by CORM-401 uncouples mitochondrial respiration and inhibits glycolysis in endothelial cells: A role for mitoBK channels. Biochim. Biophys. Acta 1847, 1297-1309 (2015).
  19. Motterlini R., Foresti R., Bassi R. & Green C. J. Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress. Free Rad. Biol. Med. 28, 1303-1312 (2000).
  20. Scapagnini G., Foresti R., Calabrese V., Giuffrida Stella A. M., Green C. J. & Motterlini R. Caffeic acid phenethyl ester and curcumin: a novel class of heme oxygenase-1 inducers. Mol. Pharmacol. 61, 554-561 (2002).
  21. Balogun E., Hoque M., Gong P., Killeen E., Green C. J., Foresti R., Alam J. & Motterlini R. Curcumin activates the heme oxygenase-1 gene via regulation of Nrf2 and the antioxidant responsive element. Biochem. J. 371, 887-895 (2003).
  22. Abuarqoub H., Foresti R., Green C. J. & Motterlini R. Heme oxygenase-1 mediates the anti-inflammatory actions of 2′-hydroxychalcone in RAW 264.7 murine macrophages. Am. J. Physiol. Cell Physiol. 290, C1092-C1099 (2006).
  23. Sawle P., Moulton B. E., Jarzykowska M., Green C. J., Foresti R., Fairlamb I. J. & Motterlini R. Structure-Activity Relationships of Methoxychalcones as Inducers of Heme Oxygenase-1. Chem. Res. Toxicol. 21, 1484-1494 (2008).
  24. Foresti R., Bains S. K., Pitchumony T. S., de Castro Bras L. E., Drago F., Dubois-Rande J. L., Bucolo C. & Motterlini R. Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells. Pharmacol. Res. 76, 132-148 (2013).
  25. Foresti R., Bucolo C., Platania C. M., Drago F., Dubois-Rande J. L. & Motterlini R. Nrf2 activators modulate oxidative stress responses and bioenergetic profiles of human retinal epithelial cells cultured in normal or high glucose conditions. Pharmacol. Res. 99, 296-307 (2015).
  26. Wilson J. L., Fayad Kobeissi S., Oudir S., Haas B., Michel B. W., Dubois-Rande J. L., Ollivier A., Martens T., Rivard M., Motterlini R. & Foresti R. Design and synthesis of novel hybrid molecules that activate the transcription factor Nrf2 and simultaneously release carbon monoxide. Chemistry 20, 14698-14704 (2014).
  27. Acquistapace A., Bru T., Lesault P. F., Figeac F., Coudert A. E., Le Coz O., Christov C., Baudin X., Auber F., Yiou R., Dubois-Rande J. L. & Rodriguez A. M. Human mesenchymal stem cells reprogram adult cardiomyocytes toward a progenitor-like state through partial cell fusion and mitochondria transfer. Stem Cells 29, 812-824 (2011).
  28. Figeac F., Lesault P. F., Le Coz O., Damy T., Souktani R., Trebeau C., Schmitt A., Ribot J., Mounier R., Guguin A., Manier C., Surenaud M., Hittinger L., Dubois-Rande J. L. & Rodriguez A. M. Nanotubular crosstalk with distressed cardiomyocytes stimulates the paracrine repair function of mesenchymal stem cells. Stem Cells 32, 216-230 (2014).

JOINING THE MOTTERLINI’S LAB

 

Dr. Motterlini’s laboratory embraces a multidisciplinary approach comprising chemistry, biochemistry, pharmacology and cell biology. Several national and international collaborations and a continuous exchange of students and research fellows enable the team to progress and consolidate its research objectives.

 

Dynamic and enthusiastic candidates interested in joining the team are strongly encouraged to contact us also for preparation of joint grant applications and fellowships. Applications should include a cover letter stating scientific interests, a CV and names and addresses of at least two referees. Please contact: Dr. Roberto Motterlini (roberto.motterlini@inserm.fr), Dr. Roberta Foresti (roberta.foresti@inserm.fr) or Dr. Anne Marie Rodriguez (anne-marie.rodriguez@inserm.fr).

Selected publications

Foresti R, Bucolo C, Platania CMB, Drago F, Dubois-Randé JL, Motterlini R. Nrf2 activators modulate oxidative stress responses and bioenergetic profiles of human retinal epithelial cells cultured in normal or high glucose conditions.

Pharmacol. Res. 2015 Sep;99:296-307.

Kaczara P, Motterlini R, Rosen GM, Augustynek B, Bednarczyk P, Szewczyk A, Foresti R, Chlopicki S. Carbon monoxide released by CORM-401 uncouples mitochondrial respiration and inhibits glycolysis in endothelial cells: a role for mitoBKCa channels.

Biochim. Biophys. Acta 2015 Oct;1847:1297-1309.

Haas B, Fayad Kobeissi S, Chrusciel S, Dubois-Randé JL, Boczkowski J, Motterlini R and Foresti R. Permanent culture of macrophages at physiological oxygen attenuates the antioxidant and immunomodulatory properties of dimethyl fumarate.

J Cell Physiol. 2015 May;230(5):1128-38.

Wilson JL, Fayad Kobeissi S, Oudir S, Haas B, Michel BW, Dubois-Randé JL, Ollivier A, Martens T, Rivard M, Motterlini R and Foresti R. Design and synthesis of novel hybrid molecules that activate the transcription factor Nrf2 and simultaneously release carbon monoxide.

Chemistry. 2014 Nov 3;20(45):14698-704.

Motterlini R and Foresti R. Heme oxygenase-1 as a target for drug discovery.

Antioxid Redox Signal. 2014 Apr 10;20(11):1810-26.

Foresti R, Bains SK, Pitchumony TS, de Castro Brás LE, Drago F, Dubois-Randé JL, Bucolo C, Motterlini R. Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells.

Pharmacol Res. 2013 Oct;76:132-48.

Yabluchanskiy A, Sawle P, Homer-Vanniasinkam S, Green CJ, Foresti R and Motterlini R. CORM-3, a carbon monoxide-releasing molecule, alters the inflammatory response and reduces brain damage in a rat model of hemorrhagic stroke.

Crit Care Med. 2012 Feb;40(2):544-52.

Desmard M, Foresti R, Morin D, Denamur E, Crook S, Mann BE, Scapens D, Montravers P, Boczkowski J and Motterlini R. Differential antibacterial activity against Pseudomonas aeruginosa by carbon monoxide-releasing molecules (CO-RMs).

Antioxid Redox Signal. 2012 Jan 15;16(2):153-63.

Motterlini R and Otterbein LE. The therapeutic potential of carbon monoxide.

Nat Rev Drug Discov. 2010 Sep;9(9):728-43.

Figeac F, Dagouassat M, Mus-Veteau I, Mahrouf-Yorgov M, Le Gouvello S, Trebeau C, Sayed A, Stern JB, Validire P, Dubois-Randé JL, Boczkowski J, Rodriguez AM. Lung fibroblasts share mesenchymal stem cell features which are altered in Chronic Obstructive Pumonary Disease via the overactivation of the Hedgehog signaling pathway.

PLoS One. 2015 Mar 27;10(3):e0121579.

Figeac F, Lesault PF, Le Coz O, Damy T, Souktani R, Trébeau C, Schmitt A, Ribot J, Mounier R Guguin A, Manier C, Surenaud M, Hittinger L, Dubois-Randé JL, Rodriguez AM. Nanotubular crosstalk with distressed cardiomyocytes stimulates the paracrine repair function of mesenchymal stem cells.

Stem Cells. 2014 Jan;32(1):216-30.

Acquistapace A, Bru T, Lesault PF, Figeac F; Coudert AE, Le Coz O, Christov C, Baudin X, Auber F, Yiou R, Dubois-Randé JL and Rodriguez AM. Human mesenchymal stem cells reprogram adult cardiomyocytes towards a progenitor-like state through partial cell fusion and mitochondria transfer.

Stem Cells. 2011 May;29(5):812-24.