Surface-modified particles loaded with CaMKII inhibitor protect cardiac cells against mitochondrial injury.
An excess of calcium (Ca2+) influx into mitochondria during mitochondrial re-energization is one of the causes of myocardial cell death during ischemic/reperfusion injury. This overload of Ca2+triggers the mitochondrial permeability transition pore (mPTP) opening which leads to programmed cell death. During the ischemic/reperfusion stage, the activated Ca2+/calmodulin-dependent protein kinase II (CaMKII) enzyme is responsible for Ca2+influx. To reduce CaMKII-related cell death, sub-micron particles composed of poly(lactic-co-glycolic acid) (PLGA), loaded with a CaMKII inhibitor peptide were fabricated. The CaMKII inhibitor peptide-loaded (CIP) particles were coated with a mitochondria targeting moiety, triphenylphosphonium cation (TPP), which allowed the particles to accumulate and release the peptide inside mitochondria to inhibit CaMKII activity. The fluorescently labeled TPP-CIP was taken up by mitochondria and successfully reduced reactive oxygen species (ROS) caused by Isoprenaline (ISO) in a differentiated rat cardiomyocyte-like cell line. When cells were treated with TPP-CIP prior to ISO exposure, they maintained mitochondrial membrane potential. The TPP-CIP protected cells from ISO-induced ROS production and decreased mitochondrial membrane potential. Thus, TPP-CIP has the potential to be used in protection against ischemia/reperfusion injury.
Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, United States; Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand. Electronic address: amaraporn.won@mahidol.ac.th.
Amaraporn
A
Wongrakpanich
Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, United States.
Angie S
AS
Morris
Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, United States.
Sean M
SM
Geary
Department of Molecular Physiology & Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA 52241, United States. Electronic address: mei-ling-joiner@uiowa.edu.
Mei-Ling A
MA
Joiner
Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, United States. Electronic address: aliasger-salem@uiowa.edu.
Aliasger K
AK
Salem
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D007545:Isoproterenol / Q000494:pharmacology; D019344:Lactic Acid / Q000737:chemistry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D009943:Organophosphorus Compounds / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013499:Surface Properties
D009943:Organophosphorus Compounds; D010455:Peptides; D020011:Protective Agents; D017382:Reactive Oxygen Species; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D007545:Isoproterenol
CaMKII; Mitochondria targeting; PLGA