ardiac surgery is associated with changes in vasomotor control which is associated with increased morbidity and mortality. This is especially true after heart operations involving cardioplegia and cardiopulmonary bypass (CPB). Recently, we have reported alterations in microvascular signal transduction and an upregulation and downregulation of specific genes in the myocardium after heart surgery involving blood cardioplegia and CPB. However, most of these studies have been performed in animal models. Since alterations in vasomotor regulation and function are critical aspects contributing to morbidity of cardioplegia and CPB, a better understandingi of thei regulationi of the (Mronarymicrovasculature of these patients may ead to improved outcomes after cardiac surgery. The goal of the proposed research is to determine the effect of cardioplegia and CPB on alterations in signal transduction associated with vascular function that occur in human patients undergoing heart surgery. Specifically, we will determine the roles of protein kinase / Dhosphatase activities, mitogen activated protein kinases, protein kinase C, and expression of inducible cyclooxygenase-2 in mediating acute changes in coronary microvascular reactivity during clinical cardiac surgery. Changes in myogenic contraction and endothelium-dependent and endothelium-independent agonist induced arteriolar vasomotor responses of the coronary microcirculation will be examined after cardioplegia and CPB, and after exposure of vessels in vitro to increased oxidative stress and inflammatory cytokines to confirm the mechanisms contributing to the findings from vessels harvested from patients. Finally, poly(ADP-ribose) polymerase (PARP) has been demonstrated to cause endothelial dysfunction and other vascular injury in patients. Thus, we will examine the changes in nitrosative stress, PARP activation and apoptosis inducing factor translocation after cardioplegia and CPB. This work will be accomplished through an exhaustive approach using molecular and cellular biology techniques to examine the protein and gene expressions involved in maintaining vascular integrity in clinical cardiac surgery involving cardioplegia / CPB. All of the methods described in the proposal have been utilized by the PI previously, and are standard and consistent preparations that have been subjected to extensive peer review. The results of these studies may have significant implications regarding the recovery of patients undergoing clinical cardiac surgery.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL046716-16
Application #
7325799
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
1992-08-01
Project End
2009-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
16
Fiscal Year
2008
Total Cost
$330,140
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Sellke, Nicholas; Kuczmarski, Alex; Lawandy, Isabella et al. (2018) Enhanced coronary arteriolar contraction to vasopressin in patients with diabetes after cardiac surgery. J Thorac Cardiovasc Surg 156:2098-2107
Potz, Brittany A; Scrimgeour, Laura A; Sabe, Sharif A et al. (2018) Glycogen synthase kinase 3? inhibition reduces mitochondrial oxidative stress in chronic myocardial ischemia. J Thorac Cardiovasc Surg 155:2492-2503
Aldosari, Sarah; Awad, Maan; Harrington, Elizabeth O et al. (2018) Subcellular Reactive Oxygen Species (ROS) in Cardiovascular Pathophysiology. Antioxidants (Basel) 7:
Liu, Yuhong; Cole, Victoria; Lawandy, Isabella et al. (2018) Decreased coronary arteriolar response to KCa channel opener after cardioplegic arrest in diabetic patients. Mol Cell Biochem 445:187-194
Sellke, Nicholas; Gordon, Caroline; Lawandy, Isabella et al. (2018) Impaired coronary contraction to phenylephrine after cardioplegic arrest in diabetic patients. J Surg Res 230:80-86
Sabe, Sharif A; Feng, Jun; Liu, Yuhong et al. (2018) Decreased contractile response of peripheral arterioles to serotonin after CPB in patients with diabetes. Surgery 164:288-293
Sellke, Frank W (2017) Bilateral Versus Single Internal Mammary Artery Bypass Grafting: Do We Have the Answer? Circulation 136:1686-1687
Potz, Brittany A; Parulkar, Anshul B; Abid, Ruhul M et al. (2017) Novel molecular targets for coronary angiogenesis and ischemic heart disease. Coron Artery Dis 28:605-613
Shafique, Ehtesham; Torina, Anali; Reichert, Karla et al. (2017) Mitochondrial redox plays a critical role in the paradoxical effects of NAPDH oxidase-derived ROS on coronary endothelium. Cardiovasc Res 113:234-246
Smits, Nicole C; Kobayashi, Takashi; Srivastava, Pratyaksh K et al. (2017) HS3ST1 genotype regulates antithrombin's inflammomodulatory tone and associates with atherosclerosis. Matrix Biol 63:69-90

Showing the most recent 10 out of 148 publications