Heart & Vascular Institute

Research

Cardiovascular Research Laboratory
Dr. Patrice Delafontaine
(504) 988-8814

Faculty:
Patrice Delafontaine, MD
Yusuke Higashi, PhD
Shaw-Yung Shai, PhD
Sergiy Sukhanov, PhD

Current, Major Projects:

NIH RO1 HL070241- INSULIN-LIKE GROWTH FACTOR-1 AND ATHEROSCLEROSIS

Cardiovascular disease is the leading cause of mortality in the Western world and its clinical manifestations result in large part from atherosclerotic lesion development, progression and destabilization. Oxidized low density lipoprotein (OxLDL) is a key pro-atherogenic molecule which induces a variety of cellular responses in the vascular wall and potentially in circulating cells, including increased oxidative/nitrosative stress, endothelial damage, transformation of macrophages into foam cells and apoptosis of smooth muscle cells (SMC). OxLDL downregulation of vascular insulin-like growth factor-1 (IGF-1) and IGF-1 receptors may play an important role in increased apoptosis and depletion of SMC in atherosclerotic plaque, contributing to plaque destabilization. IGF-1 infusion in rodents increases circulating endothelial progenitor cells, reduces circulating cytokines, upregulates endothelial nitric oxide synthase and reduces atherosclerotic plaque burden. These findings suggest that IGF-1 may also alter plaque composition to a more stable and less inflammatory phenotype. The long-term role of this project is to understand how IGF-1 impacts atherosclerotic plaque development and stability by obtaining insights into its anti-oxidant, anti-inflammatory and pro-repair effects. Specific aims are to: 1. Demonstrate that IGF-1 reduces atherosclerosis via an anti-oxidant effect that includes induction of endothelial nitric oxide synthase expression and activity, reduction in inflammatory cytokines and prevention of foam cell formation. 2. Demonstrate that IGF-1 reduces atherosclerosis via its ability to promote vascular repair by stimulating the recruitment of vascular progenitor cells, including endothelial progenitor cells (EPC). 3. Demonstrate that the anti-atherosclerotic effects of IGF-1 are mediated via endocrine and autocrine/ paracrine mechanisms. These studies will provide key mechanistic insights into the effects of IGF-1 on the pathophysiology of atherosclerosis and provide a rationale for new therapies targeted at improving the clinical outcome and quality of life of patients afflicted with coronary, peripheral vascular and cerebrovascular disease.

NIH RO1 HL080682- ANGIOTENSIN II, IGF-1 AND SKELETAL MUSCLE ATROPHY

Skeletal muscle atrophy occurs in a variety of diseases including congestive heart failure (CHF), a leading cause of cardiovascular mortality and morbidity. Skeletal muscle atrophy is an important predictor of poor outcome in CHF, but mechanisms are poorly understood. The generalized neurohumoral excitation that is a hallmark of CHF includes activation of the renin-angiotensin-aldosterone system (RAS). We have evidence that angiotensin II (ang II) produces skeletal muscle atrophy in rodents via activation of the ubiquitin-protea- some proteolytic pathway and increased apoptosis. Concomitantly ang II reduces skeletal muscle insulin-like growth factor-1 (IGF-1) and IGF-1 signaling via the PI 3-kinase/Akt pathway and increases muscle caspase-3 activity leading to actin cleavage. Transgenic expression of IGF-1 in muscle prevents these changes and ang II induced muscle loss. We have preliminary similar findings in a pressure-overload heart failure model. To elucidate molecular mechanisms whereby ang II and pressure-overload heart failure produce skeletal muscle atrophy we propose: 1. To characterize altered IGF-1 signaling mechanisms mediating ang II or pressure-overload heart failure induced skeletal muscle atrophy. 2. To characterize molecular mechanisms whereby ang II or pressure-overload heart failure triggers muscle proteolysis, specifically mechanisms leading to actin cleavage and increased ubiquitinization. 3. To demonstrate that ang II or pressure-overload heart failure induced skeletal muscle atrophy can be prevented by expression of a muscle-specific IGF-1 transgene. 4. To characterize the role of stem cells in the ability of autocrine IGF-1 to prevent ang II induced skeletal muscle atrophy. These findings should provide novel insights into molecular mechanisms of skeletal muscle atrophy in CHF, and lay the basis for development of new therapeutic strategies.

Recent Publications:

1. Sukhanov S, Semprun-Prieto L, Yoshida T, Michael Tabony A, Higashi Y, Galvez S, Delafontaine P. Angiotensin II, Oxidative Stress and Skeletal Muscle Wasting. Am J Med Sci. 2011. PMID 21747283.
2. Semprun-Prieto LC, Sukhanov S, Yoshida T, Rezk BM, Gonzalez-Villalobos RA, Vaughn C, Michael Tabony A, Delafontaine P. Angiotensin II induced catabolic effect and muscle atrophy are redox dependent. Biochem Biophys Res Commun. 2011;409(2):217-21. PMID 21570954, PMCID: 3109128.
3. Shlipak MG, Lash JP, Yang W, Teal V, Keane M, Cappola T, Keller C, Jamerson K, Kusek J, Delafontaine P, He J, Miller ER, 3rd, Schreiber M, Go AS. Symptoms characteristic of heart failure among CKD patients without diagnosed heart failure. J Card Fail. 2011;17(1):17-23. PMID 21187260, PMCID: 3011973.
4. Shanmugam P, Valente AJ, Prabhu SD, Venkatesan B, Yoshida T, Delafontaine P, Chandrasekar B. Angiotensin-II type 1 receptor and NOX2 mediate TCF/LEF and CREB dependent WISP1 induction and cardiomyocyte hypertrophy. J Mol Cell Cardiol. 2011. PMID 21376054.
5. Shai SY, Sukhanov S, Higashi Y, Vaughn C, Rosen CJ, Delafontaine P. Low Circulating Insulin-Like Growth Factor I Increases Atherosclerosis in Apoe-Deficient Mice. Am J Physiol Heart Circ Physiol. 2011. PMID 21335474.
6. Reddy VS, Valente AJ, Delafontaine P, Chandrasekar B. Interleukin-18/WNT1-Inducible signaling pathway protein-1 signaling mediates human saphenous vein smooth muscle cell proliferation. J Cell Physiol. 2011. PMID 21321938.
7. Kandavar R, Higashi Y, Chen W, Blackstock C, Vaughn C, Sukhanov S, Sander GE, Roffidal LE, Delafontaine P, Giles TD. The effect of nebivolol versus metoprolol succinate extended release on asymmetric dimethylarginine in hypertension. J Am Soc Hypertens. 2011. PMID 21251896.
8. Yoshida T, Semprun-Prieto L, Sukhanov S, Delafontaine P. IGF-1 prevents ANG II-induced skeletal muscle atrophy via Akt- and Foxo-dependent inhibition of the ubiquitin ligase atrogin-1 expression. Am J Physiol Heart Circ Physiol. 2010;298(5):H1565-70. PMID 20228261, PMCID: 2867436.
9. Venkatesan B, Valente AJ, Prabhu SD, Shanmugam P, Delafontaine P, Chandrasekar B. EMMPRIN activates multiple transcription factors in cardiomyocytes, and induces interleukin-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-kappaB andMKK7/JNK/AP-1 signaling. J Mol Cell Cardiol. 2010;49(4):655-63. PMID 20538003.
10. Venkatesan B, Prabhu SD, Venkatachalam K, Mummidi S, Valente AJ, Clark RA, Delafontaine P, Chandrasekar B. WNT1-inducible signaling pathway protein-1 activates diverse cell survival pathways and blocks doxorubicin-induced cardiomyocyte death. Cell Signal.
11. 2010;22(5):809-20. PMID 20074638, PMCID: 2885703.
12. Shai SY, Sukhanov S, Higashi Y, Vaughn C, Kelly J, Delafontaine P. Smooth muscle cell-specific insulin-like growth factor-1 overexpression in Apoe-/- mice does not alter atherosclerotic plaque burden but increases features of plaque stability. Arterioscler Thromb Vasc Biol. 2010;30(10):1916-24. PMID 20671230, PMCID: 2940990.
13. Reddy VS, Prabhu SD, Mummidi S, Valente AJ, Venkatesan B, Shanmugam P, Delafontaine P, Chandrasekar B. Interleukin-18 induces EMMPRIN expression in primary cardiomyocytes via JNK/Sp1 signaling and MMP-9 in part via EMMPRIN and through AP-1 and NF-kappaB activation. Am J Physiol Heart Circ Physiol. 2010;299(4):H1242-54. PMID 20693392, PMCID: 2957343.
14. Higashi Y, Sukhanov S, Anwar A, Shai SY, Delafontaine P. IGF-1, oxidative stress and atheroprotection. Trends Endocrinol Metab. 2010;21(4):245-54. PMID 20071192, PMCID: 2848911.
15. Higashi Y, Holder K, Delafontaine P. Thiazolidinediones up-regulate insulin-like growth factor-1 receptor via a peroxisome proliferator-activated receptor gamma-independent pathway. J Biol Chem. 2010;285(47):36361-8. PMID 20843793.
16. Delafontaine P, Anwar A. Vitamin C and percutaneous coronary intervention. JACC Cardiovasc Interv. 2010;3(2):230-2. PMID 20170882.