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Angiotensin II‐preconditioning is associated with increased PKCɛ/PKCδ ratio and prosurvival kinases in mitochondria
Author(s) -
Nuñez Rebeca,
Javadov Sabzali,
Escobales Nelson
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.680.3
Subject(s) - chelerythrine , cardioprotection , protein kinase c , protein kinase b , angiotensin ii , mptp , mitochondrial permeability transition pore , ischemic preconditioning , chemistry , pharmacology , p38 mitogen activated protein kinases , angiotensin ii receptor type 1 , mapk/erk pathway , kinase , medicine , endocrinology , microbiology and biotechnology , ischemia , biology , apoptosis , receptor , biochemistry , programmed cell death , dopaminergic , dopamine
Recent studies indicate that angiotensin II replicates the cardioprotective effects of ischemic preconditioning (IPC). However, the cellular mediators of angiotensin II preconditioning (APC) remain to be fully understood. In this study, Langendorff‐perfused rat hearts were subjected to IPC, APC or both (IPC/APC) followed by ischemia‐reperfusion (IR), to determine the protein expression of PKCɛ, PKCδ, Akt, Erk1/2, JNK, p38 MAPK and GSK‐3β in mitochondria, and the permeability transition pore (mPTP) opening. IPC, APC and IPC/APC increased the percent recovery of left ventricular developed pressure (LVDP), and reduced lactate dehydrogenase (LDH) release compared to controls. These effects were associated with marked increases in the mitochondrial PKCɛ/PKCδ ratio, Akt, Erk1/2 and JNK levels and mPTP inhibition. GSK‐3β levels were unaffected by the treatment protocols. Chelerythrine (5 μM), a pan‐PKC inhibitor, abolished the enhancements of PKCɛ but increased PKCδ expression, and inhibited Akt, Erk1/2, and JNK protein levels. The drug however, did not affect cardioprotection by APC and IPC/APC. Losartan (10 μM), an angiotensin II type 1 receptor (AT1‐R) blocker, abolished the APC‐stimulated LVDP increase and inhibited the protein levels of PKCɛ, Akt, Erk1/2, JNK, and p38. Both drugs reduced ischemic contracture and LDH release, and abolished the inhibition of mPTP by the preconditioning protocols. These results suggest that the cardioprotection induced by APC and IPC/APC involves an AT1‐R‐dependent, translocation of PKCɛ and downstream survival kinases to the mitochondria leading to mPTP inhibition. The observation of cardioprotection in chelerythrine‐treated hearts, suggests that reduced PKCɛ/PKCδ ratio might attenuate calcium overload and contracture‐induced damage at reperfusion. Support or Funding Information This study was supported by the NIH RCMI Program grant No. G12M007600, NHLBI grant SC1HL118669 (SJ), and the University of Puerto Rico.