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Research Interests

The main goal of the laboratory is to analyze the mechanisms whereby metabolic disorders such as obesity, diabetes and lipodystrophy, lead to cardiovascular disease. More specifically, we are interested in determining the contribution of leptin, a hormone secreted by the adipose tissue, to vascular disease and hypertension. A major focus of the lab is to understand the sex-specificity of the mechanisms leading to cardiovascular disease in obesity and diabetes and to understand how metabolic disorders abrogate the protective effects of female sex hormones.  All experiments are conducted in close collaboration with physicians and involve an integrative approach consisting of a wide range of physiological, pharmacological and molecular methods, and involving genetically engineered mouse models of disease.

Research Projects

1. Contribution of the “leptin-adrenal-endothelial mineralocorticoid receptor axis” to cardiovascular disease in premenopausal women.

While women are initially view as protected from cardiovascular disease until menopause, compelling evidence indicates that obesity and high salt diet abrogate the protective effects of female sex hormones. One of the major goals of the laboratory is to test whether increases in leptin signaling could contribute to cardiovascular disease in premenopausal women. While combining the use of genetically engineered mouse models with in vitro experiments and studies in discarded human tissues, we have identified the adipokine leptin as a new direct regulator of aldosterone production by demonstrating that leptin acts in the adrenal glands to increase aldosterone synthase (CYP11B2) expression via calcium-dependent mechanisms and stimulate aldosterone production (Figure 1). We extended our findings by showing that leptin-mediated aldosterone production plays a major role in the development of cardiovascular disease in obese female by impairing endothelial function. These findings led to the proposal of the new concept that obesity induces hypertension via sex-specific mechanisms: leptin-mediated sympatho-activation in males and leptin-induced aldosterone production in females (Figure 2). More recently we demonstrated that the female sex hormone progesterone predisposes women to leptin- and aldosterone-induced vascular dysfunction and hypertension via upregulating endothelial mineralocorticoid receptor expression (Figure 3). Current projects aim at further understanding the origin(s) of the sex differences and the molecular mechanisms involved in MR regulation.

Schematic illustrating that leptin is a direct regulator of Aldosterone Synthase expression and aldosterone production.
Schematic illustrating that obesity leads to hypertension via sex specific mechanisms: leptin-mediated sympatho-activation in males and leptin-mediated aldosterone production in females.
Schematic illustrating that progesterone regulates endothelial mineralocorticoid expression via activation of endothelial progesterone receptors and that this mechanism predisposes to obesity-associated endothelial dysfunction

2. Leptin control of endothelial oxidative stressSchematic illustrating that leptin regulates endothelial function via reducing endothelial Nox1 and CCR5 expression.

Conditions associated with reduced fat mass such as congenital generalized lipodystrophy, type I diabetes, and HIV-related lipodystrophy are a cause of reduced NO bioavailability and endothelial dysfunction. Based on the evidence that leptin regulates endothelium NO bioavailability in males, a question raised by the laboratory is whether reduced leptin levels consequent to low-fat mass contributes to endothelial dysfunction. Using a mouse model of congenital generalized lipodystrophy (mice deficient in Berardinelly Seip gene, Bscl2), but also with mouse model mimicking HIV-associated lipodystrophy (ritonavir treatment) we revealed that deficiency or insufficient leptin levels cause endothelial dysfunction by mechanisms involving reduced activation of endothelial leptin receptor. We showed that reduced endothelial leptin signaling decreases peroxisome proliferator-activated receptor-gamma (PPARg) expression and increases in NADPH oxidase NOX1, C-C chemokine receptor type 5 (CCR5) and vascular inflammation in male animals (Figure 4). Current investigations aim to understand (1) the sex specificity of these mechanisms, (2) the molecular links between leptin, PPARg, NOX1 and CCR5 and (3) the identity of the fat depot responsible for the positive effects of leptin on endothelial function.


Schematic illustrating that HIV-derived proteins and combination antiretroviral therapy contributes to HIV-associated cardiovascular disease.

3. Mechanisms of vascular disease and hypertension in HIV.

Thanks to the advent of combination antiretroviral therapy (cART), life expectancy has markedly increased in patients living with HIV, who now exhibit accelerated development of cardiovascular disease. A major question raised is the contribution of repressed viral infection and cART to HIV-associated hypertension, endothelial dysfunction and atherosclerosis. Using a transgenic mouse model mimicking repressed viral infection (Tg26 mouse), the laboratory is investigating the contribution of both HIV viral proteins and cART to endothelial dysfunction, hypertension and atherosclerosis (Figure 5). As patients with HIV now present with obesity, an objective of the laboratory is also to understand the mechanisms whereby HIV viral proteins and cART affect metabolic function and energy expenditure.

 

 

 

 

 

 

 

Spotlight Publications

Huby, G. Antonova, J. Groenendyk, CE. Gomez-Sanchez, WB. Bollag, JA. Filosa, EJ. Belin de Chantemèle. The Adipocyte-Derived Hormone Leptin is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis. (2015) Circulation. 132(22):2134-45

Huby AC, Otvos L, Belin de Chantemèle EJ. Leptin Induces Hypertension and Endothelial Dysfunction via Aldosterone-Dependent Mechanisms in Obese Female Mice. (2016). Hypertension. 67(5):1020-8

Faulkner JL, Harwood D, Bender L, Shrestha L, Brands MW, Morwitzer MJ, Kennard S, Antonova G, Belin de Chantemèle EJ. Lack of suppression of aldosterone production leads to salt sensitive hypertension in female but not male Balb/C mice. (2018) Hypertension, 72:1397-1406

Faulkner JL, Kennard S, Huby AC, Antonova G, Lu Q, Jaffe IZ, Patel VS, Fulton DJR, Belin de Chantemèle EJ. Progesterone predisposes females to obesity-associated leptin-mediated endothelial dysfunction via upregulating endothelial mineralocorticoid receptor expression. (2019) Hypertension, 74(3):678-686

Bruder-Nascimento T, Kennard S, Faulkner JL, Antonova G, Haigh S, Patel VS, Fulton DJR, Chen W, Belin de Chantemèle EJ. Leptin replacement therapy restores endothelial function, vascular adrenergic contractility and heart rate in a mouse model of congenital generalized lipodystrophy (CGL). (2019) Hypertension, 74(6):1399-1408. PMID: 31656096 PMCID: PMC6886673


    

Recent Publications

  1. Faulkner JL, Harwood, D, Lluch E, Kennard S, Antonova G, Clere N, Belin de Chantemèle Dietary sodium restriction sex-specifically impairs endothelial function via mineralocorticoid receptor-dependent reduction in NO bioavailability in Balb/C mice. Am J Physiol Heart Circ Physiol. 2021 Jan 1;320(1):H211-H220. PMID: 33095056
  2. Faulkner JL, Lluch E, Kennard S, Antonova G, Jaffe IZ, Belin de Chantemèle Selective deletion of endothelial mineralocorticoid receptor protects from vascular dysfunction in sodium restricted female mice. Biol Sex Differ. 2020 Nov 23;11(1):64. PMID: 33228767 
  3. Bruder-Nascimento T, Kress TC, Kennard S, Belin de Chantemèle EJ. The HIV protease inhibitor Ritonavir impairs endothelial function via reduction in adipose mass and endothelial leptin receptor-dependent increases in Nox1, CCR5 and inflammation. J Am Heart Assoc. 2020 Oct 20;9(19):e018074 PMID: 33003981 
  4. Tritz R, Benson T, Harris V, Hudson FZ, Mintz J, Zhang H, Kennard S, Chen W, Stepp DW Csanyi G, Belin de Chantemèle EJ, Weintraub N, Stansfield BK. Nf1 Heterozygous Mice Recapitulate the Anthropometric and Metabolic Features of Human Neurofibromatosis Type 1. Transl Res. 2020 Aug 8:S1931-5244(20)30197-3 PMID: 32781282
  5. Legeay S, Fautrat P, Norman JB, Antonova G, Kennard S, Bruder-Nascimento T, Patel VS, Faure S, Belin de Chantemèle EJ. Selective deficiency in endothelial PTP1B protects from diabetes and endoplasmic reticulum stress-associated endothelial dysfunction via preventing endothelial cell apoptosis. Biomed Pharmacother. 2020 Jul;127:110200. PMID: 32417688
  6. Bruder-Nascimento T, Callera, GC, Montezano, AC. Belin de Chantemèle EJ, Tostes RC, Touyz, RM. Atorvastatin inhibits pro-inflammatory actions of aldosterone in vascular smooth muscle cells by reducing oxidative stress. (2019) Life Sciences, 15;221:29-34. Bruder-Nascimento T, Ekeledo OJ, Anderson R, Le HB, Belin de Chantemèle EJ. Long Term High Fat Diet Treatment: An Appropriate Approach to Study the Sex-Specificity of the Autonomic and Cardiovascular Responses to Obesity in Mice. (2017) Phys. 26;8:32.
  7. Thompson JA, Larion S, Mintz JD, Belin de Chantemele EJ, Fulton DJ, Stepp DW. Genetic Deletion of NADPH Oxidase 1 Rescues Microvascular Function in Mice with Metabolic Disease. (2017) Circ Res. 121(5):502-511.
  8. Lin HP, Singla B, Ghoshal P, Faulkner JL, Cherian-Shaw M, O'Connor PM, She JX, Belin de ChantemeleEJ, Csányi G. Identification of novel macropinocytosis inhibitors using a rational screen of Food and Drug Administration-approved drugs. (2018) Br J Pharmacol. 175(18) :3640-3655.
  9. Horimatsu T, Patel AS, Prasad R, Reid LE, Benson TW, Zarzour A, Ogbi M, Bruder do Nascimento T, Belin de ChantemeleE, Stansfield BK, Lu XY, Kim HW, Weintraub NL. Remote Effects of Transplanted Perivascular Adipose Tissue on Endothelial Function and Atherosclerosis. (2018) Cardiovasc Drugs Ther. 32(5):503-510.
  10. Bruder-Nascimento T, Bence KK, and Belin de Chantemèle EJ. POMC Ptp1b Deletion increases energy expenditure and impairs endothelial function via TNF-α dependent mechanisms. (2016) Clin Sci. 130(11):881-93

 

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