Cardioprotective kinase signaling to subsarcolemmal and interfibrillar mitochondria is mediated by caveolar structures.
The demonstration that caveolin-3 overexpression reduces myocardial ischemia/reperfusion injury and our own finding that multiprotein signaling complexes increase in mitochondria in association with caveolin-3 levels, led us to investigate the contribution of caveolae-driven extracellular signal-regulated kinases 1/2 (ERK1/2) on maintaining the function of cardiac mitochondrial subpopulations from reperfused hearts subjected to postconditioning (PostC). Rat hearts were isolated and subjected to ischemia/reperfusion and to PostC. Enhanced cardiac function, reduced infarct size and preserved ultrastructure of cardiomyocytes were associated with increased formation of caveolar structures, augmented levels of caveolin-3 and mitochondrial ERK1/2 activation in PostC hearts in both subsarcolemmal (SSM) and interfibrillar (IFM) subpopulations. Disruption of caveolae with methyl-β-cyclodextrin abolished cardioprotection in PostC hearts and diminished pho-ERK1/2 gold-labeling in both mitochondrial subpopulations in correlation with suppression of resistance to permeability transition pore opening. Also, differences between the mitochondrial subpopulations in the setting of PostC were evaluated. Caveolae disruption with methyl-β-cyclodextrin abolished the cardioprotective effect of postconditioning by inhibiting the interaction of ERK1/2 with mitochondria and promoted decline in mitochondrial function. SSM, which are particularly sensitive to reperfusion damage, take advantage of their location in cardiomyocyte boundary and benefit from the cardioprotective signaling driven by caveolae, avoiding injury propagation.
Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología "Ignacio Chávez", Juan Badiano No. 1, Sección XVI, 14080, Ciudad de México, México. wramsesgarcia@gmail.com.
Wylly Ramsés
WR
García-Niño
Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología "Ignacio Chávez", Juan Badiano No. 1, Sección XVI, 14080, Ciudad de México, México.
Francisco
F
Correa
Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología "Ignacio Chávez", Juan Badiano No. 1, Sección XVI, 14080, Ciudad de México, México.
Julia Isabel
JI
Rodríguez-Barrena
Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", 14000, Ciudad de México, México.
Juan Carlos
JC
León-Contreras
Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología "Ignacio Chávez", Juan Badiano No. 1, Sección XVI, 14080, Ciudad de México, México.
Mabel
M
Buelna-Chontal
Departamento de Patología, Instituto Nacional de Cardiología "Ignacio Chávez", 14080, Ciudad de México, México.
Elizabeth
E
Soria-Castro
Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", 14000, Ciudad de México, México.
Rogelio
R
Hernández-Pando
Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, 04510, Ciudad de México, México.
José
J
Pedraza-Chaverri
Departamento de Biomedicina Cardiovascular, Instituto Nacional de Cardiología "Ignacio Chávez", Juan Badiano No. 1, Sección XVI, 14080, Ciudad de México, México. azazuetam@yahoo.com.
Cecilia
http://orcid.org/0000-0003-1068-316X
C
Zazueta
D000818:Animals; D021941:Caveolae / Q000378:metabolism*; D004195:Disease Models, Animal; D015151:Immunoblotting; D057775:Ischemic Postconditioning; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore
Cardioprotection; Caveolae; Mitochondrial ERK1/2; Mitochondrial subpopulations; Postconditioning