With prevalence as high as 55% for individuals aged 55 and older in United States, hypertension is a major risk factor contributing to cardiovascular diseases (CVD) and global mortality, hence remaining an increasingly important medical and public health issue. The role of the renin-angiotensin system (RAS) in the maintenance of normal blood pressure (BP) and in neuro-cardiovascular dysregulation leading to hypertension has been firmly established. Angiotensin (Ang)-II, by means of its type 1 receptor (AT₁R), promotes increased sympathetic activity, salt and water reabsorption, vasoconstriction, aldosterone and vasopressin release and inflammation, all contributing to hypertension. By converting Ang-II into Ang-(1-7), ACE2 (Angiotensin Converting Enzyme type 2) acts as a pivotal player in the ACE2/Ang-(1-7)/Mas receptor compensatory axis of the RAS, capable of preventing the progression and reducing hypertension.

Project 1: Targeting ACE2 ubiquitination in hypertension (NIH funded)

However, our group was the first to show post-translational impairment of endogenous ACE2 in hypertension. Notably, our laboratories reported that Ang-II mediates ACE2 ubiquitination and degradation in lysosomes. The therapeutic potential of targeting this mechanism has not been investigated. This project aims at providing new therapeutic strategies to target ACE2 ubiquitination, originally described by our group, for the treatment of hypertension. The efficacy of these strategies will be evaluated by their ability to prevent ACE2 internalization and degradation and preserve ACE2 compensatory activity in both central nervous system and vasculature within males and females, in the context of Ang-II-mediated hypertension. This proposal uses unique and novel mouse models with neuron-specific expression or deletion of hypothalamic neuronal AT₁R and PVN-specific deletion of ACE2. In addition, we combine ACE2 ubiquitination mutants with superior enzymatic activity and a new adeno-associated virus encoding an ubiquitin-deficient ACE2 protein to assess the beneficial effects of preventing ACE2 degradation in hypertension. We also combine some of these specific KO with optogenetic approaches, allowing us to selectively activate neuronal populations.

Project 2: Targeting ADAM17 maturation in resistant hypertension (NIH funded)

While numerous overexpression studies, from our group and others, have established the benefits of ACE2 (Angiotensin Converting Enzyme type 2) in preventing the progression and improving the treatment of hypertension (HTN) in experimental models, our group was the first to demonstrate that ADAM17 (A Disintegrin And Metalloprotease) mediates ACE2 shedding in neurogenic HTN, thus reducing ACE2 compensatory activity in mice and humans. ADAM17-mediated ACE2 shedding, a process by which the protein ectodomain is cleaved from the plasma membrane and secreted into the surrounding milieu. ADAM17 is thought to mediate neuroinflammation through soluble TNFα, IL-6 trans-signaling, CX3CL1 and other cytokines, yet this mechanism has not been studied in neurogenic HTN. DOCA-salt HTN is associated with increased levels of TNFα, IL-6 and reduced ACE2 activity in the brain, while deletion of ADAM17 from neurons reduces BP, restores ACE2 activity and decreases pro-inflammatory cytokines. Recent work shows that ADAM17 maturation is tightly regulated by rhomboid proteins in the brain (iRhom1 in neurons and iRhom2 in microglia), opening the door for novel targeting strategies. Accordingly, we hypothesize that targeting ADAM17 maturation will reverse sympatho-excitation and neuro-inflammation in neurogenic HTN. This project aims at targeting ADAM17 maturation in neurogenic HTN. In addition to clarifying how ADAM17 activation spreads through and affects neuronal networks involved in cardiovascular regulation, we will test our novel targeting strategy and evaluate how it affects ADAM17 transport and function. To achieve this goal, we propose a translational approach that will i) characterize the mechanisms and extent of ADAM17-mediated shedding in pre-sympathetic neurons, and ii) determine its specificity and relevance in neuroinflammation leading to neurogenic HTN. We use a combination of approaches such as: 1) iRhom1/2 silencing in vivo and in vitro, 2) in vitro activation and gain/loss of function studies using human neurons and microglia and new conditional mouse model (Cx3CR1-ADAM17-Td-tomato KO, 3) adoptive transfer of exosomes from hypertensive mice to the brain of normotensive animals, 4) single cell genotyping with digital droplet qPCR, 5) retrograde labeling to characterize BP- and immune system-relevant neurons and 6) wireless fiber photometry to assess Ca++ imaging as an index of neuronal activity in conscious mice.

Project 3: miRNA targeting of hypertension and metabolic pathways (VA funded)

More than a thousand miRNA families have been identified to regulate RAS genes expression, where their dysregulation has been associated with hypertension, cardiac ischemia and aging. Our previous data show that perinatal programming with hypercaloric diet (HCD) leads to increased BP and glycemic levels, as well as hypothalamic inflammation. This cardiometabolic phenotype of programmed mice is associated with differential expression of hypothalamic miRNA controlling angiotensin (Ang)-II type 1 (AT₁R) and type 2 (AT₂R) receptors compared to regular diet (RD)-fed mice. Interestingly, AT₁R-targeting miRNA also showed the same expression pattern in an HCD-fed model that exhibits obesity and hyperglycemia. Based on these observations, the central hypothesis of this project is that dysregulation of miRNA targeting brain AT₁R and AT₂R is involved in the pathogenesis of CMD. To test this hypothesis, we will use state-of-the-art in vitro and in vivo molecular and pharmacological tools to manipulate key miRNA, targeting AT₁R and AT₂R, in hypertensive and obese/diabetic mice. We will take advantage of validated models of Ang-II infusion to induce hypertension and HCD feeding to induce obesity and hyperglycemia while manipulating miRNA expression.

Please, find a complete list of the Lazartigues' lab publications here.

 

Former Lab Members:

• Mazher Mohammed (Postdoctoral Associate: 2020-2022). Postdoctoral Researcher at Mount Sinai.
• Clara Berdasco (Postdoctoral Associate: 2020-2022). Postdoctoral Researcher in Rutgers, New Jersey.
• Navya Lakkappa (Postdoctoral Associate: 2019-2022). Postdoctoral Researcher in Dublin, Ireland.
• Md Abdul Awoal (Master Student: 2019-2020). Research Associate, Tulane University, New Orleans, LA.
• Charlotte Pearson (Research Associate: 2020-2021). Research Associate, BioInnovation Center, New Orleans, LA.
• Tamara M. Morris (Research Associate: 2019-2020). Graduate student, Interdisciplinary Program, LSUHSC-NO in New Orleans, LA.
• Nilgun Kuru (Visiting Professor: 2019-2020). Associate Professor, Department of Anatomy, Selcuk University, Konya, Turkey.
• Jiaxi Xu, PhD (Postdoctoral Associate: 2014-2019). Assistant Professor at Xi'an Jiaotong University, PR China.
• Snigdha Mukerjee, PhD (PhD Student: 2014-2019). Postdoctoral Researcher at Vanderbilt University, Nashville, TN.
• Alynne Carvalho-Galvao (Exchange PhD Student: 2017-2018). PhD student at the Universidade Federal da Paraiba, Joao Pessoa, Brazil.
• Tyler Basting PhD (Postdoctoral Associate: 2016-2018). Medical Writer in Manassas, VA.
• Alberto Mendoza, MD (Clinician Scientist: 2013-2015). Cardiology Pediatrician at the University of Texas, Corpus Christi, TX.
• Thyago Moreira de Queiroz (Exchange PhD Student: 2013-2014).Professor at the Federal University de Ceara, Fortaleza, Brazil.
• Matthew Deshotels, MSc (Master’s Student: 2012-2013). Internal Medicine Resident at Baylor College in Houston, TX.
• Harshita Chodavarapu, PhD (PhD Student: 2012-2017). Pharmacometrician at Certara.
• Melissa D. Scroggin, MSc (Master’s Student: 2011-2013). Doctor of Physical Therapy, New Orleans, LA.
• Kim Brint Pedersen, PhD (Postdoctoral Associate: 2010-2015). Research Assistant Professor of Pharmacology at LSUHSC-NO in New Orleans, LA
• Srinivas Sriramula, PhD (Postdoctoral Associate: 2010-2015). Assistant Professor of Pharmacology at the East Carolina University in Greenville, NC.
• Kavaljit Chhabra, PhD (PhD Student: 2009-2013). Assistant Professor at the University of Rochester Medical Center, Rochester, NY
• Ping Xu, MD-PhD (Postdoctoral Associate: 2009-2010). Medical Affairs Manager at Danaher, San Francisco Bay Area, CA.
• Yanhui Cai, MSc (Graduate Student: 2009-2010). Scientist at Gilead Pharmaceuticals, CA.
• Sharell M. Bindom, PhD (MD-PhD Student: 2006-2009). Neonatologist in Hollywood, FL.
• Huijing Xia, PhD (Postdoctoral Associate: 2006-2011). Research Assistant Professor of Pharmacology at LSUHSC-NO in New Orleans, LA.
• Yumei Feng, MD-Ph.D. (Postdoctoral Associate: 2006-2010). Professor of Pharmacology and Physiology & Cell Biology at the University of Nevada School of Medicine in Reno, NV.