Nsini A Umoh, Robin K Walker, Richard M Millis, Mustafa Al-Rubaiee, Pandu R Gangula, Georges E Haddad
{"title":"降钙素基因相关肽通过PI3K/Akt和MAPK信号通路调控氧化应激,调控心肌细胞存活","authors":"Nsini A Umoh, Robin K Walker, Richard M Millis, Mustafa Al-Rubaiee, Pandu R Gangula, Georges E Haddad","doi":"","DOIUrl":null,"url":null,"abstract":"<p><p>CGRP and specific CGRP receptors are found in the heart where they produce positive-inotropic and anti-apoptotic effects, key adaptations to exercise and cardiovascular disease. PI3K/Akt and MAPK signaling imbalances are associated with cardiomyocyte pathologies; however, the effects of CGRP on these pathways are unclear. Therefore, we hypothesized that CGRP modulates inotropic and apoptotic adaptations of cardiomyocytes by regulating PI3K/Akt and MAPK/ERK signaling balances. We treated cardiomyocytes with combinations of CGRP, PI3K/Akt and MAPK signaling agonists and antagonists. We evaluated expression of the mRNA and proteins levels of survival signaling molecules related to the PI3K/Akt and MAPK and measured apoptosis by caspase 3/7 activity. CGRP<sub>1-37</sub> decreased Akt, NFκB, SOD-3 and increased ERK1/2 and p38 MAPK expressions, which was antagonized by CGRP<sub>8-37</sub>. Akt-negative construct transfection, Ad.Akt(K179M), inhibited the CGRP<sub>1-37</sub>-induced increment in MAPK expressions. A PI3K-antagonist treatment with LY294002 or CGRP<sub>1-37</sub>/Ad.Akt(K179M) co-treatment alleviated the CGRP-increased caspase activity and -decrements in SOD-3. These findings demonstrate a CGRP negative effect on the PI3K/Akt signaling pathway and CGRP receptor-induced crosstalk between PI3K/Akt and MAPK in normal cardiomyocytes. Future studies to differentiate CGRP effects on intracellular signal transduction mechanisms in pathological conditions will elucidate the significance of CGRP in, and provide novel therapeutic targets for, heart failure.</p>","PeriodicalId":90435,"journal":{"name":"Annals of clinical and experimental hypertension","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251564/pdf/nihms581689.pdf","citationCount":"0","resultStr":"{\"title\":\"Calcitonin Gene-Related Peptide Regulates Cardiomyocyte Survival through Regulation of Oxidative Stress by PI3K/Akt and MAPK Signaling Pathways.\",\"authors\":\"Nsini A Umoh, Robin K Walker, Richard M Millis, Mustafa Al-Rubaiee, Pandu R Gangula, Georges E Haddad\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>CGRP and specific CGRP receptors are found in the heart where they produce positive-inotropic and anti-apoptotic effects, key adaptations to exercise and cardiovascular disease. PI3K/Akt and MAPK signaling imbalances are associated with cardiomyocyte pathologies; however, the effects of CGRP on these pathways are unclear. Therefore, we hypothesized that CGRP modulates inotropic and apoptotic adaptations of cardiomyocytes by regulating PI3K/Akt and MAPK/ERK signaling balances. We treated cardiomyocytes with combinations of CGRP, PI3K/Akt and MAPK signaling agonists and antagonists. We evaluated expression of the mRNA and proteins levels of survival signaling molecules related to the PI3K/Akt and MAPK and measured apoptosis by caspase 3/7 activity. CGRP<sub>1-37</sub> decreased Akt, NFκB, SOD-3 and increased ERK1/2 and p38 MAPK expressions, which was antagonized by CGRP<sub>8-37</sub>. Akt-negative construct transfection, Ad.Akt(K179M), inhibited the CGRP<sub>1-37</sub>-induced increment in MAPK expressions. A PI3K-antagonist treatment with LY294002 or CGRP<sub>1-37</sub>/Ad.Akt(K179M) co-treatment alleviated the CGRP-increased caspase activity and -decrements in SOD-3. These findings demonstrate a CGRP negative effect on the PI3K/Akt signaling pathway and CGRP receptor-induced crosstalk between PI3K/Akt and MAPK in normal cardiomyocytes. Future studies to differentiate CGRP effects on intracellular signal transduction mechanisms in pathological conditions will elucidate the significance of CGRP in, and provide novel therapeutic targets for, heart failure.</p>\",\"PeriodicalId\":90435,\"journal\":{\"name\":\"Annals of clinical and experimental hypertension\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2014-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251564/pdf/nihms581689.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of clinical and experimental hypertension\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of clinical and experimental hypertension","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Calcitonin Gene-Related Peptide Regulates Cardiomyocyte Survival through Regulation of Oxidative Stress by PI3K/Akt and MAPK Signaling Pathways.
CGRP and specific CGRP receptors are found in the heart where they produce positive-inotropic and anti-apoptotic effects, key adaptations to exercise and cardiovascular disease. PI3K/Akt and MAPK signaling imbalances are associated with cardiomyocyte pathologies; however, the effects of CGRP on these pathways are unclear. Therefore, we hypothesized that CGRP modulates inotropic and apoptotic adaptations of cardiomyocytes by regulating PI3K/Akt and MAPK/ERK signaling balances. We treated cardiomyocytes with combinations of CGRP, PI3K/Akt and MAPK signaling agonists and antagonists. We evaluated expression of the mRNA and proteins levels of survival signaling molecules related to the PI3K/Akt and MAPK and measured apoptosis by caspase 3/7 activity. CGRP1-37 decreased Akt, NFκB, SOD-3 and increased ERK1/2 and p38 MAPK expressions, which was antagonized by CGRP8-37. Akt-negative construct transfection, Ad.Akt(K179M), inhibited the CGRP1-37-induced increment in MAPK expressions. A PI3K-antagonist treatment with LY294002 or CGRP1-37/Ad.Akt(K179M) co-treatment alleviated the CGRP-increased caspase activity and -decrements in SOD-3. These findings demonstrate a CGRP negative effect on the PI3K/Akt signaling pathway and CGRP receptor-induced crosstalk between PI3K/Akt and MAPK in normal cardiomyocytes. Future studies to differentiate CGRP effects on intracellular signal transduction mechanisms in pathological conditions will elucidate the significance of CGRP in, and provide novel therapeutic targets for, heart failure.