Coronary arteriolar function is highly dependent on the integrity of endothelial cells (EC) and vascular smooth muscle cells (VSMC). Type 2 diabetes is associated with increased prevalence of ischemic heart disease, generally related to coronary artery disease that is associated with increased morbidity and death in diabetic patients. Epidermal growth factor receptor (EGFR) tyrosine kinase, of the many factors involved in cell growth and migration has been shown to be critical in the development of microvascular myogenic tone expressed as microvascular constriction in response to pressure increases. Our studies show an exacerbation of EGFR tyrosine kinase phosphorylation in coronary arteriolar from type 2 diabetic mice (db-/db- mice lacking leptin receptor gene) associated with coronary arteriolar dysfunction characterized by a reduced endothelial-dependent relaxation and potentiation of myogenic tone. Interestingly, in vivo inhibition of EGFR tyrosine kinase in db-/db- mice significantly improves coronary arteriolar function. Thus, enhanced EGFR tyrosine kinase in diabetes could be a critical up stream signal leading to a myriad of downstream signaling including oxidative stress, NFkB and PARP-1. More importantly, oxidative stress, nuclear factor kappa Beta (NFkB-transcriptional and nuclear factor) and poly(ADP-ribose)polymerase (PARP-1 nuclear factor), which are highly implicated in the etiology and progression of type 2 diabetes, could be critical in coronary arteriolar dysfunction in diabetes. Our preliminary data indicate an increase in oxidative stress (superoxide;O2.-), p65- NFkB activity and PARP-1 activity in coronary arterioles from db-/db- mice. Despite these connections, there has been no link determined between the coronary arteriolar pathology of diabetes with EGFR tyrosine kinase, oxidative stress, NFkB and PARP-1 pathway. Therefore, our central hypothesis is that exacerbation of EGFR tyrosine kinase phosphorylation leads to the increased ROS, NFkB and PARP activity, which in turn are responsible for coronary arteriolar dysfunction in type 2 diabetes. We will determine that:
Aim 1. EGFR tyrosine kinase inhibition reduces O2.-, p65-NFkB and PARP activity, and improves coronary arteriolar function in db-/db- mice;
Aim 2. Inhibition of O2.- production or scavenging of O2.- in db-/db- mice improves coronary arteriolar EC and VSMC dysfunction;
Aim 3. Increased p65-NFkB and PARP-1 activities are critical in coronary arteriolar dysfunction in db-/db- mice. The successful completion of this project will determine the mechanisms how exacerbation of EGFR tyrosine kinase leads to the increased oxidative stress, NFkB and PARP-1 activity, which in turn are responsible for coronary arteriolar dysfunction, and will provide new insight into the vasculopathy mechanisms in diabetes.

Public Health Relevance

Type 2 diabetes mellitus and cardiovascular disease contribute to a high proportion of the burden of disease in the UNITED STATES. The goal of our studies is to determine how increased Epidermal Growth Factor Receptor tyrosine kinase activity compromises coronary arteriolar function in type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL095566-04
Application #
8383472
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Ershow, Abby
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2013
Total Cost
$345,183
Indirect Cost
$109,563
Name
Eastern Virginia Medical School
Department
Physiology
Type
Schools of Medicine
DUNS #
058625146
City
Norfolk
State
VA
Country
United States
Zip Code
23501
Kassan, Modar; Choi, Soo-Kyoung; Galán, Maria et al. (2015) Nuclear factor kappa B inhibition improves conductance artery function in type 2 diabetic mice. Diabetes Metab Res Rev 31:39-49
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Zhang, Xuexin; Zhang, Wei; González-Cobos, José C et al. (2014) Complex role of STIM1 in the activation of store-independent Orai1/3 channels. J Gen Physiol 143:345-59
Kassan, Modar; Choi, Soo-Kyoung; Galán, Maria et al. (2014) Enhanced p22phox expression impairs vascular function through p38 and ERK1/2 MAP kinase-dependent mechanisms in type 2 diabetic mice. Am J Physiol Heart Circ Physiol 306:H972-80
Zhang, Xuexin; Gonzalez-Cobos, Jose C; Schindl, Rainer et al. (2013) Mechanisms of STIM1 activation of store-independent leukotriene C4-regulated Ca2+ channels. Mol Cell Biol 33:3715-23
Motiani, Rajender K; Hyzinski-Garcia, Maria C; Zhang, Xuexin et al. (2013) STIM1 and Orai1 mediate CRAC channel activity and are essential for human glioblastoma invasion. Pflugers Arch 465:1249-60
Motiani, Rajender K; Zhang, Xuexin; Harmon, Kelly E et al. (2013) Orai3 is an estrogen receptor ?-regulated Ca²? channel that promotes tumorigenesis. FASEB J 27:63-75
Kassan, Modar; Choi, Soo-Kyoung; Galan, Maria et al. (2013) Enhanced NF-*B activity impairs vascular function through PARP-1-, SP-1-, and COX-2-dependent mechanisms in type 2 diabetes. Diabetes 62:2078-87
Shinde, Arti V; Motiani, Rajender K; Zhang, Xuexin et al. (2013) STIM1 controls endothelial barrier function independently of Orai1 and Ca2+ entry. Sci Signal 6:ra18
Kassan, Modar; Wecker, Andrea; Kadowitz, Philip et al. (2013) CD4+CD25+Foxp3 regulatory T cells and vascular dysfunction in hypertension. J Hypertens 31:1939-43

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