Mary Garry Lab

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Mary GarryIn my laboratory, we study the role of primary afferent neurons in the control of cardiovascular responses to exercise. We are interested in the basic mechanisms that drive the exercise pressor reflex (EPR) under normal, physiological conditions but we also have a great deal of interest in the control of the EPR in disease.

Previous studies have suggested that the exaggerated increases in blood pressure, sympathetic nerve activity, and vascular resistance to exercise in patients with cardiovascular disease are due, in part, to an over active EPR. However, the mechanisms controlling these cardiovascular responses are not easily studied as few disease models exist in cats and dogs (the major species being used to study the EPR) and mechanistic studies in humans have encountered feasibility problems.

The rodent is an attractive candidate for the study of the EPR as disease models (e.g. heart failure, hypertension, and diabetes) are readily available or easily produced. Additionally, more genomic information is currently known for rodents compared to larger mammals presenting the opportunity to study the mechanisms of this reflex at the level of cellular and molecular physiology.

Research Projects

Determining the role of TRPv1 dysregulation in cardiovascular responses to exercise in heart failure:

Exaggerations in the cardiovascular responses to exercise in heart failure patients are mediated, in part, by an over active exercise pressor reflex (EPR). The EPR is a mechanism where blood pressure and heart rate increase in response to contraction-induced activation of primary afferent neurons and reflexive changes in autonomic outflow. LHI--MGarry_img_tensionTransduc Importantly, exaggerations in the EPR correlate with morbidity and mortality in heart failure patients. We developed a novel animal model to study the EPR in rats with heart failure. With this model, we have determined that the EPR is overactive in rats in heart failure just as it is in humans. We have also identified several mechanisms which contribute to this overactivity. First, we have determined that the TRPv1 receptor (previously known as the capsaicin receptor) mediates, in part, the EPR in the rat. In spite of an exaggerated EPR, the group IV afferent neurons are less responsive to capsaicin in heart failure when compared to sham treated controls. We have also demonstrated that ablation of group IV afferent neurons (in non-cardiomyopathic animals) results in an overactive EPR similar LHI--MGarry_img_cellsGlowto that observed in heart failure. Additionally, we have determined that group III afferent neurons mediate the exaggerated EPR in the absence of group IV afferent responsiveness. Based on these collective findings, we hypothesize that reduced responsiveness in group IV afferent neurons leads to increased activation of group III afferent neurons and results in an overactive EPR in heart failure. We are currently engaged in studies that explore the role that the TRPv1 down regulation or desensitization plays in the abnormal EPR in heart failure.

Determining factors that dysregulate the TRPv1 in heart failure:

To date, the known activators of TRPv1 include a diverse set of chemical entities as well as physical stimuli such as heat. In addition to capsaicin, numerous other vanilloids as well as many non-vanilloids are TRPv1 agonists. Lipids, including several lipoxygenase products and the endogenous cannabinoid, anandamide can also activate TRPv1. In addition to heat and lipids, protons (i.e., acids) can also be considered endogenous modulators of TRPv1 as they can potentiate, directly activate, and at higher concentrations, even block TRPv1. In addition, recent evidence indicates that adenosine can directly activate the TRPv1. We have recently determined that TRPv1 activation mediates the EPR in rats. Ongoing studies in our lab currently address whether the TRPv1 contributes to the EPR abnormalities in the pathological states.

Determining factors that mark the group III afferent neuron:

Direct evaluation of the contribution of group III afferent neurons to the EPR in health and disease is essential for understanding the mechanisms that mediate abnormalities in the EPR. We are currently identifying factors that serve to mark this population of afferent neurons in the periphery.

Publications

1. Smith SA, Mitchell JH, Garry M.G (2001) Electrically induced static exercise elicits a pressor response in the decerebrate rat. J Physiol. 537(Pt 3):961-70.

2. Tanaka H, Yoshida T, Miyamoto N, Motoike T, Kurosu H, Shibata K, Yamanaka A, Williams SC, Richardson JA, Tsujino N, Garry MG, Lerner, MR, King DS, O'Dowd BF, Sakurai T, Yanagisawa M. (2003) Characterization of a family of endogenous neuropeptide ligands for the G protein- couple receptors GPR7 and GPR8. Proc. Natl. Acad. Sci. 100:6251-6256.

3. Potts, J.T., Paton, J.F.R., Mitchell, J.H., Garry, M.G., Anguelov, P.T., Lee, S.M. (2003) Contraction sensitive skeletal muscle A-delta and C fiber afferents inhibit arterial baroreceptor signalling in the nucleus of the solitary tract: role of intrinsic GABA interneurons. Neuroscience 119:201-14.

4. Mammen, P.A., Kanatous, S.B., Yuhanna, I.S., Shaul, P.W., Garry, M.G., Balaban, R.S. Garry, D.J. (2003) Hypoxia-induced left ventricular dystunction in myoglobin deficient mice. Am. J. Physiol. Heart Circ. Physiol. (July 24, 2003; ePub ahead of print).

5. Smith, S.A., Mammen, P.P.A, Mitchell, J.H., Garry, M.G. (2003) The role of the exercise pressor reflex in rats with dilated cardiomyopathy. Circulation 108: 1126-1132.

6. Smith, SA; Williams, MA; Mitchell, JH; Mammen, PPA; and MG Garry (2005) The Capsaicin Sensitive Afferent Neuron in Skeletal Muscle is Abnormal in Heart Failure. Circulation 111:2056-65.

7.Kelly MA; Beuckmann, CT; Williams, SC; Sinton, CM; Motoike, T; Richardson, JA; Hammer, RE; MG Garry, and Yanagisawa, M (2005) Neuropeptide B deficient mice demonstrate hyperalgesia in response to inflammatory pain. Proc. Natl. Acad. Sci., 102:9942-9947.

8. Smith S.A., J.H. Mitchell, R.H. Naseem, and Garry, M.G. (2005) The Mechanoreflex Mediates the Exaggerated Exercise Pressor Reflex in Heart Failure. Circulation 2005 Oct 11;112(15):2293-300.

9. Smith SA, Mitchell JH, and Garry M.G. (2006) The mammalian exercise pressor reflex in health and disease. Exp Physiol. 91:89-102.

10. Maass, D.L., R.H. Naseem, M.G. Garry, and J.W. Horton (2006) Echocardiography assessment of myocardial function after burn injury. Shock 4:363-9.

11. Smith SA, Williams MA, Leal AK, Mitchell JH, Garry MG (2007) Exercise pressor reflex function is altered in spontaneously hypertensive rats. J Physiol.577:1009-20.

12. Sadek H, B Hannack, E Choe, J Wang, S Latif, MG Garry, DJ Garry, J Longgood, DE Frantz, EN Olson, J Hsieh and JW Schneider (2007) Cardiogenic small molecules that enhance stem cell function in myocardial repair. Proc Natl Acad Sci 105:6063-8.

13. Williams, MA, Smith, SA, O’Brien, DE; Mitchell, JH, and MG Garry (2008) The group IV afferent neuron expresses multiple receptor alterations in cardiomyopathy in rat: evidence at the cannabinoid CB1 receptor. J. Physiol. 586:835-45.

14. Martin, CM, A Ferdous, T Gallardo, C Humphries, H Sadek, J Garcia, MG Garry, LI Szweda, and DJ Garry (2008) HIF-2alpha transactivates Abcg2 and promotes cytoprotection in cardiac SP cells. Circ Res. 102:1075-81.

14. Leal, AK, MA. Williams, MG. Garry, JH. Mitchell, and SA. Smith (2008) Evidence for functional alterations in the skeletal muscle mechanoreflex and the metaboreflex in hypertensive rats. Am J Physiol Heart Circ Physiol. 295:H1429-38.

15. Sadek H, Hannack B, Choe E, Wang J, Latif S, Garry MG, Garry DJ, Longgood J,Frantz DE, Olson EN, Hsieh J, Schneider JW. (2008) Cardiogenic small molecules that enhance myocardial repair by stem cells. Proc Natl Acad Sci. 105:6063-8.

16. HA. Sadek, CM. Martin, SS. Latif , MG. Garry, DJ. Garry. Bone-Marrow-Derived Side Population Cells for Myocardial Regeneration (2009) J. of Cardiovasc. Trans. Res., In Press.

17. S.A. Smith, A.K. Leal, M.A. Williams, M.N. Murphy, J.H. Mitchell, and MG Garry (2010) The TRPv1 receptor is a mediator of the exercise pressor reflex in rats. J. Physiol. In Press.

Lab Members

Maggie Robledo
Scientist

Qinglu Li
Scientist

Collaborative Members

Elizabeth Braunlin, M.D., Ph.D.

Contact Info

Email
garry002@umn.edu

Phone
612.626.2773

Fax
612.624.8118

Office Address
4-147 Cancer & Cardiovascular Research Building