The long term goal of this proposal is to identify those mechanisms involved in the cardioprotective effect of light in the red to near infrared range (630-1,000 nm;NIR). Our laboratory has found that brief exposure (3 min) of dog, rabbit and mouse myocardium to 670 nm wavelength light generated by a light-emitting diode at the point of reperfusion following a 30 minute coronary artery occlusion results in a significant reduction in infarct size. Moreover, striking differences in the mechanisms involved in NIR-mediated cardioprotection have been discovered compared to ischemic or pharmacological postconditioning. This may allow application of NIR for cardioprotection in disease models such as diabetes where pharmacological postconditioning has proven to be ineffective. We propose to test the overall hypothesis that NIR treatment of myocardium, immediately following a prolonged ischemic period, involves the release of nitric oxide (NO) from heme-containing proteins. The resulting, and, importantly, site-specific release of NO targets protective signaling pathways and mitochondrial metabolism.
Three Specific Aims will be used to identify the potential contributions of NO containing myoglobin, hemoglobin and/or cytochrome c oxidase to the cardioprotective effect of NIR in the non-diabetic and diabetic mouse.
Specific Aim I will investigate the effects of NIR on cellular and tissue preservation and function and on mitochondrial bioenergetics in the diabetic and non-diabetic mouse, and compare the effect with a conventional NO-donor.
Specific Aim II will study the release of NO from heme-binding partners using mainly biophysical methodologies in cell-free, cellular and tissue models of reperfusion injury.
Specific Aim III will explore the source of NO that is largely responsible for the observed cardioprotective effect of NIR and expand the application of NIR to a non- or minimally-invasive animal model. Throughout this proposal we will make use of relevant murine knockouts that are either commercially available or that we have secured from outside collaborators. The mechanisms responsible for the ability of NIR to attenuate the damage to ischemic myocardium during reperfusion have not been characterized and the results of this work will add significantly to the fields of cardiovascular biology and photobiology. Importantly, the use of NIR for reperfusion injury has the potential for rapid translation to the clinic given its relatively safe profile.

Public Health Relevance

Reperfusion injury of the ischemic myocardium represents a significant problem in the United States. Several pharmacological agents have been identified to protect the heart from reperfusion injury but translation to the clinical setting has yielded conflicting results. Near infrared light, alone or in combination with other pharmacological adjuvants could offer a unique strategy to mitigate the damage that occurs to the ischemic myocardium during reperfusion of the coronary artery.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098490-04
Application #
8495785
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2010-06-15
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$358,142
Indirect Cost
$122,522
Name
Medical College of Wisconsin
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Cain, Cindy L; Riess, Matthias L; Gettrust, Lynn et al. (2014) Malignant hyperthermia crisis: optimizing patient outcomes through simulation and interdisciplinary collaboration. AORN J 99:301-8; quiz 309-11
Nabbi, Raha; Gadicherla, Ashish K; Kersten, Judy R et al. (2014) Genetically determined mitochondrial preservation and cardioprotection against myocardial ischemia-reperfusion injury in a consomic rat model. Physiol Genomics 46:169-76
Riess, Matthias L; Matsuura, Timothy R; Bartos, Jason A et al. (2014) Anaesthetic Postconditioning at the Initiation of CPR Improves Myocardial and Mitochondrial Function in a Pig Model of Prolonged Untreated Ventricular Fibrillation. Resuscitation 85:1745-51
Muravyeva, Maria; Baotic, Ines; Bienengraeber, Martin et al. (2014) Cardioprotection during diabetes: the role of mitochondrial DNA. Anesthesiology 120:870-9
Tanaka, Katsuya; Kersten, Judy R; Riess, Matthias L (2014) Opioid-induced cardioprotection. Curr Pharm Des 20:5696-705
Bienengraeber, Martin; Pellitteri-Hahn, Molly; Hirata, Naoyuki et al. (2013) Quantitative characterization of changes in the cardiac mitochondrial proteome during anesthetic preconditioning and ischemia. Physiol Genomics 45:163-70
Riess, Matthias L; Podgoreanu, Mihai V (2013) Intralipid: the new magic bullet in cardioprotection? Anesthesiology 118:1237-8
Hirata, Naoyuki; Shim, Yon Hee; Pravdic, Danijel et al. (2011) Isoflurane differentially modulates mitochondrial reactive oxygen species production via forward versus reverse electron transport flow: implications for preconditioning. Anesthesiology 115:531-40
Sedlic, Filip; Pravdic, Danijel; Hirata, Naoyuki et al. (2010) Monitoring mitochondrial electron fluxes using NAD(P)H-flavoprotein fluorometry reveals complex action of isoflurane on cardiomyocytes. Biochim Biophys Acta 1797:1749-58