Journal of Cardiobiology
Research Article
Targeting Protein Kinase C Beta II to Reduce Myocardial Ischemia–Reperfusion Injury
Nair A1, Beale MA1, Dean TC1, Singh SG1, Michaels M1, Baker A1, Madison IT1, Lloyd M1, Castro J1, Dang J1, Metellus D1, Melnik J1, Le A1, Chen Q1, Barsotti R1, and Young LH1,2*
1Department of Bio-Medical Sciences, Philadelphia College of Osteopathic
Medicine (PCOM), Philadelphia, PA 19131, USA
2Young Therapeutics, LLC, Philadelphia, PA 19152, USA
2Young Therapeutics, LLC, Philadelphia, PA 19152, USA
*Address for Correspondence:Lindon H. Young, Department of Bio-Medical Sciences Philadelphia College of Osteopathic Medicine 4170 City Avenue Philadelphia, PA 19131 USA. E-mail Id: lindonyo@pcom.edu
Submission: 29 May, 2026
Accepted: 13 August, 2026
Published: 18 August, 2026
Copyright: © 2026 Nair A, et al. This is an open access article distributed
under the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.
Keywords:Myocardial Infarction; Cardioprotection; Yt-003; Reactive Oxygen
Species; Nicotinamide Adenine Dinucleotide Phosphate Oxidase 2; Receptor for
Activated C Kinase 1 (Rack1).
Abstract
Myocardial infarction (MI) remains a leading cause of morbidity and mortality
worldwide and is most commonly caused by coronary artery occlusion. Although
restoration of coronary blood flow is essential to preserve viable myocardium,
reperfusion paradoxically induces additional injury through mechanisms involving
reactive oxygen species (ROS) generation and inflammation, collectively termed
myocardial ischemia–reperfusion (MIR) injury. Protein kinase C beta II (PKCβII) has
emerged as a potential therapeutic target in MIR because of its role in regulating
oxidative and inflammatory signaling pathways; however, the relative effects of
PKCβII activation versus inhibition remain incompletely defined. Accordingly, we
evaluated a selective cell-permeable PKCβII inhibitor (YT-003) and a selective PKCβII
activator using complementary in vitro and ex vivo MIR models.
Rat polymorphonuclear leukocytes (PMNs) were pretreated with selective PKCβII modulators and chemically stimulated to generate superoxide (SO) to assess ROSgenerating capacity. Human umbilical vein endothelial cells (HUVECs) underwent hypoxia and reoxygenation, with treatment given at the onset of reoxygenation, and viability was assessed. Isolated rat hearts underwent global ischemia followed by reperfusion in a Langendorff preparation, with treatment administered at reperfusion onset; cardiac functional recovery and infarct size were measured.
YT-003 significantly reduced PMN-derived SO release, improved HUVEC survival after hypoxia–reoxygenation, decreased myocardial infarct size, and increased left ventricular functional recovery compared with controls. In contrast, the selective PKCβII activator did not significantly alter outcomes in any of the experimental models.
These findings indicate that selective PKCβII inhibition with YT-003 is protective in complementary in vitro and ex vivo MIR models. The activator data indicate a lack of efficacy for this particular peptide, rather than excluding a protective role for PKCβII activation more generally. These results are hypothesis-generating and require confirmation in clinically relevant in vivo models before the therapeutic potential of PKCβII inhibition after MI can be defined.
Rat polymorphonuclear leukocytes (PMNs) were pretreated with selective PKCβII modulators and chemically stimulated to generate superoxide (SO) to assess ROSgenerating capacity. Human umbilical vein endothelial cells (HUVECs) underwent hypoxia and reoxygenation, with treatment given at the onset of reoxygenation, and viability was assessed. Isolated rat hearts underwent global ischemia followed by reperfusion in a Langendorff preparation, with treatment administered at reperfusion onset; cardiac functional recovery and infarct size were measured.
YT-003 significantly reduced PMN-derived SO release, improved HUVEC survival after hypoxia–reoxygenation, decreased myocardial infarct size, and increased left ventricular functional recovery compared with controls. In contrast, the selective PKCβII activator did not significantly alter outcomes in any of the experimental models.
These findings indicate that selective PKCβII inhibition with YT-003 is protective in complementary in vitro and ex vivo MIR models. The activator data indicate a lack of efficacy for this particular peptide, rather than excluding a protective role for PKCβII activation more generally. These results are hypothesis-generating and require confirmation in clinically relevant in vivo models before the therapeutic potential of PKCβII inhibition after MI can be defined.