{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T03:57:10Z","timestamp":1784606230730,"version":"3.55.0"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100005725","name":"National Plan for Science, Technology and Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004919","name":"King Abdulaziz City for Science and Technology","doi-asserted-by":"publisher","award":["12-MED3221-02"],"award-info":[{"award-number":["12-MED3221-02"]}],"id":[{"id":"10.13039\/501100004919","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Considering the complementary nature of signalling mechanisms and the therapeutic effects of nebivolol, a \u03b21-adrenoreceptor antagonist, and valsartan, an angiotensin receptor blocker (ARB), here we aimed to investigate whether nebivolol\/valsartan combination would complement the cardioprotective effects of nebivolol on angiotensin II (ANG II)-induced pathology in H9c2 cardiomyoblasts.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>H9c2 cardiomyoblasts were used to investigate the protective effects of nebivolol and nebivolol and valsartan combination against ANG II-induced pathology. Reactive oxygen species (ROS) generation was determined by 2\u2032,7\u2032-dichlorofluorescein diacetate (DCFDA) and MitoSOX Red staining. Real-time PCR and immunoblotting were employed to quantify the changes in mRNA and protein expression levels, respectively.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Key findings<\/jats:title>\n                  <jats:p>Our data revealed that pretreatment with nebivolol and nebivolol\/valsartan combination significantly reduced ANG II-induced oxidative stress and mTORC1 signalling. Concurrently, ANG II-induced activation of inflammatory cytokines and fetal gene expressions were significantly suppressed by nebivolol and nebivolol\/valsartan combination. Pretreatment with nebivolol and nebivolol\/valsartan combination alleviated ANG II-induced impairment of mitochondrial biogenesis by restoring the gene expression levels of PGC-1\u03b1, TFAM, NRF-1 and SIRT3. Our data further show that nebivolol and nebivolol\/valsartan combination mediated up-regulation in mitochondrial biogenesis is accompanied by decrease in ANG II-stimulated mitochondrial ROS generation as well as increase in expression of mitochondrial fusion genes MFN2 and OPA1, indicative of improved mitochondrial dynamics.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Summary<\/jats:title>\n                  <jats:p>These findings suggest that both nebivolol and nebivolol\/valsartan combination exert protective effects on ANG II-induced mitochondrial dysfunction by alleviating its biogenesis and dynamics. Moreover, addition of valsartan to nebivolol do not produce any additive effects compared with nebivolol alone on ANG II-induced cardiac pathology.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jpp\/rgab124","type":"journal-article","created":{"date-parts":[[2021,8,3]],"date-time":"2021-08-03T11:19:08Z","timestamp":1627989548000},"page":"1520-1529","source":"Crossref","is-referenced-by-count":11,"title":["Comparative beneficial effects of nebivolol and nebivolol\/valsartan combination against mitochondrial dysfunction in angiotensin II-induced pathology in H9c2 cardiomyoblasts"],"prefix":"10.1093","volume":"73","author":[{"given":"Rukhsana","family":"Gul","sequence":"first","affiliation":[{"name":"Obesity Research Center, College of Medicine, King Saud University , Riyadh ,","place":["Kingdom of Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nouf","family":"Alsalman","sequence":"additional","affiliation":[{"name":"Obesity Research Center, College of Medicine, King Saud University , Riyadh ,","place":["Kingdom of Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arwa","family":"Bazighifan","sequence":"additional","affiliation":[{"name":"Obesity Research Center, College of Medicine, King Saud University , Riyadh ,","place":["Kingdom of Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Assim A","family":"Alfadda","sequence":"additional","affiliation":[{"name":"Obesity Research Center, College of Medicine, King Saud University , Riyadh ,","place":["Kingdom of Saudi Arabia"]},{"name":"Department of Medicine, College of Medicine, King Saud University , Riyadh ,","place":["Kingdom of Saudi Arabia"]},{"name":"Strategic Center for Diabetes Research, College of Medicine, King Saud University , Riyadh ,","place":["Kingdom of Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,11,1]]},"reference":[{"key":"2024103012143798600_CIT0001","doi-asserted-by":"crossref","first-page":"ti","DOI":"10.1016\/j.jacc.2009.05.066","article-title":"Nebivolol: the somewhat-different beta-adrenergic receptor blocker","volume":"54","author":"M\u00fcnzel","year":"2009","journal-title":"J Am Coll Cardiol"},{"key":"2024103012143798600_CIT0002","doi-asserted-by":"crossref","first-page":"733","DOI":"10.2174\/157016110793563861","article-title":"Current place of beta-blockers in the treatment of hypertension","volume":"8","author":"Bielecka-Dabrowa","year":"2010","journal-title":"Curr Vasc Pharmacol"},{"key":"2024103012143798600_CIT0003","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1016\/j.jacc.2008.05.057","article-title":"Beta-blockers for primary prevention of heart failure in patients with hypertension insights from a meta-analysis","volume":"52","author":"Bangalore","year":"2008","journal-title":"J Am Coll Cardiol"},{"key":"2024103012143798600_CIT0004","doi-asserted-by":"crossref","first-page":"b1665","DOI":"10.1136\/bmj.b1665","article-title":"Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies","volume":"338","author":"Law","year":"2009","journal-title":"BMJ"},{"key":"2024103012143798600_CIT0005","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1159\/000339565","article-title":"Regulation of overnutrition-induced cardiac inflammatory mechanisms","volume":"2","author":"Gul","year":"2012","journal-title":"Cardiorenal Med"},{"issue":"2","key":"2024103012143798600_CIT0006","doi-asserted-by":"crossref","first-page":"H2341","DOI":"10.1152\/ajpheart.01126.2011","article-title":"Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the transgenic (mRen","volume":"302","author":"Ma","year":"2012","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2024103012143798600_CIT0007","doi-asserted-by":"crossref","first-page":"2683","DOI":"10.1016\/j.jacc.2011.09.033","article-title":"Beta3-adrenoreceptor stimulation ameliorates myocardial ischemia-reperfusion injury via endothelial nitric oxide synthase and neuronal nitric oxide synthase activation","volume":"58","author":"Aragon","year":"2011","journal-title":"J Am Coll Cardiol"},{"key":"2024103012143798600_CIT0008","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1016\/j.yjmcc.2010.02.011","article-title":"Beta 3-adrenoreceptor regulation of nitric oxide in the cardiovascular system","volume":"48","author":"Moens","year":"2010","journal-title":"J Mol Cell Cardiol"},{"key":"2024103012143798600_CIT0009","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4103\/2045-9912.202904","article-title":"Exercise training provides cardioprotection by activating and coupling endothelial nitric oxide synthase via a \u03b2(3)-adrenergic receptor-AMP-activated protein kinase signaling pathway","volume":"7","author":"Barr","year":"2017","journal-title":"Medical Gas Res"},{"key":"2024103012143798600_CIT0010","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/j.1365-2125.1994.tb04342.x","article-title":"Nitric oxide mediated venodilator effects of nebivolol","volume":"38","author":"Bowman","year":"1994","journal-title":"Br J Clin Pharmacol"},{"key":"2024103012143798600_CIT0011","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1590\/S0100-879X2002000900001","article-title":"Recent advances in angiotensin II signaling","volume":"35","author":"Touyz","year":"2002","journal-title":"Braz J Med Biol Res"},{"key":"2024103012143798600_CIT0012","doi-asserted-by":"crossref","first-page":"H77","DOI":"10.1152\/ajpheart.01355.2007","article-title":"A novel signaling pathway of ADP-ribosyl cyclase activation by angiotensin II in adult rat cardiomyocytes","volume":"295","author":"Gul","year":"2008","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2024103012143798600_CIT0013","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1093\/cvr\/cvn232","article-title":"Inhibition of ADP-ribosyl cyclase attenuates angiotensin II-induced cardiac hypertrophy","volume":"81","author":"Gul","year":"2009","journal-title":"Cardiovasc Res"},{"key":"2024103012143798600_CIT0014","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1159\/000343456","article-title":"RAS-mediated adaptive mechanisms in cardiovascular tissues: confounding factors of RAS blockade therapy and alternative approaches","volume":"2","author":"Gul","year":"2012","journal-title":"Cardiorenal Med"},{"key":"2024103012143798600_CIT0015","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1002\/oby.21227","article-title":"Regulation of cardiac miR-208a, an inducer of obesity, by rapamycin and nebivolol","volume":"23","author":"Gul","year":"2015","journal-title":"Obesity (Silver Spring)"},{"key":"2024103012143798600_CIT0016","doi-asserted-by":"crossref","first-page":"H2009","DOI":"10.1152\/ajpheart.00522.2007","article-title":"Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance","volume":"293","author":"Cooper","year":"2007","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2024103012143798600_CIT0017","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1177\/1753944716642677","article-title":"Cardiac remodelling and RAS inhibition","volume":"10","author":"Ferrario","year":"2016","journal-title":"Ther Adv Cardiovasc Dis"},{"key":"2024103012143798600_CIT0018","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s002280050259","article-title":"Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man","volume":"52","author":"Flesch","year":"1997","journal-title":"Eur J Clin Pharmacol"},{"key":"2024103012143798600_CIT0019","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/0167-0115(95)00085-P","article-title":"Binding of valsartan to mammalian angiotensin AT1 receptors","volume":"59","author":"de Gasparo","year":"1995","journal-title":"Regul Pept"},{"key":"2024103012143798600_CIT0020","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1111\/j.1523-1755.2005.00145.x","article-title":"Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications","volume":"67","author":"Wolf","year":"2005","journal-title":"Kidney Int"},{"key":"2024103012143798600_CIT0021","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1161\/01.HYP.0000158261.86674.8e","article-title":"Impact of obesity on 24-hour ambulatory blood pressure and hypertension","volume":"45","author":"Kotsis","year":"2005","journal-title":"Hypertension"},{"key":"2024103012143798600_CIT0022","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.coph.2012.12.002","article-title":"Beta blockers, nitric oxide, and cardiovascular disease","volume":"13","author":"Vanhoutte","year":"2013","journal-title":"Curr Opin Pharmacol"},{"key":"2024103012143798600_CIT0023","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1016\/S0140-6736(14)60614-0","article-title":"Efficacy and safety of nebivolol and valsartan as fixed-dose combination in hypertension: a randomised, multicentre study","volume":"383","author":"Giles","year":"2014","journal-title":"Lancet"},{"key":"2024103012143798600_CIT0024","doi-asserted-by":"crossref","first-page":"212531","DOI":"10.7573\/dic.212531","article-title":"Combination therapy in the treatment of hypertension","volume":"7","author":"Guerrero-Garc\u00eda","year":"2018","journal-title":"Drugs Context"},{"key":"2024103012143798600_CIT0025","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.amjmed.2008.09.038","article-title":"Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials","volume":"122","author":"Wald","year":"2009","journal-title":"Am J Med"},{"key":"2024103012143798600_CIT0026","first-page":"119","article-title":"Enalapril and atenolol in essential hypertension: attenuation of hypotensive effects in combination","volume":"10","author":"Wing","year":"1988","journal-title":"Clin Exp Hypertens A"},{"key":"2024103012143798600_CIT0027","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1111\/j.1751-7176.2010.00341.x","article-title":"Effect of combining extended-release carvedilol and lisinopril in hypertension: results of the COSMOS study","volume":"12","author":"Bakris","year":"2010","journal-title":"J Clin Hypertens (Greenwich)"},{"key":"2024103012143798600_CIT0028","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.bbrc.2013.07.055","article-title":"Nebivolol stimulates mitochondrial biogenesis in 3T3-L1 adipocytes","volume":"438","author":"Huang","year":"2013","journal-title":"Biochem Biophys Res Commun"},{"key":"2024103012143798600_CIT0029","doi-asserted-by":"crossref","first-page":"F775","DOI":"10.1152\/ajprenal.00233.2012","article-title":"Nebivolol-induced vasodilation of renal afferent arterioles involves \u03b23-adrenergic receptor and nitric oxide synthase activation","volume":"303","author":"Feng","year":"2012","journal-title":"Am J Physiol Renal Physiol"},{"key":"2024103012143798600_CIT0030","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1097\/00005344-200401000-00022","article-title":"Antioxidant activity of nebivolol in the rat aorta","volume":"43","author":"de Groot","year":"2004","journal-title":"J Cardiovasc Pharmacol"},{"issue":"2","key":"2024103012143798600_CIT0031","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1161\/01.CIR.102.6.677","article-title":"Nebivolol: a third-generation beta-blocker that augments vascular nitric oxide release: endothelial beta(","volume":"102","author":"Broeders","year":"2000","journal-title":"Circulation"},{"key":"2024103012143798600_CIT0032","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.pcad.2009.05.002","article-title":"Clinical impact of left ventricular hypertrophy and implications for regression","volume":"52","author":"Artham","year":"2009","journal-title":"Prog Cardiovasc Dis"},{"key":"2024103012143798600_CIT0033","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1093\/cvr\/cvn098","article-title":"Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha","volume":"79","author":"Ventura-Clapier","year":"2008","journal-title":"Cardiovasc Res"},{"key":"2024103012143798600_CIT0034","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1042\/bse0470069","article-title":"Regulation of mitochondrial biogenesis","volume":"47","author":"Jornayvaz","year":"2010","journal-title":"Essays Biochem"},{"key":"2024103012143798600_CIT0035","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/acel.12538","article-title":"Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease","volume":"16","author":"Ansari","year":"2017","journal-title":"Aging Cell"},{"key":"2024103012143798600_CIT0036","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1161\/CIRCHEARTFAILURE.108.812099","article-title":"Control by circulating factors of mitochondrial function and transcription cascade in heart failure: a role for endothelin-1 and angiotensin II","volume":"2","author":"Garnier","year":"2009","journal-title":"Circ Heart Fail"},{"key":"2024103012143798600_CIT0037","doi-asserted-by":"crossref","first-page":"196","DOI":"10.3109\/08037051.2010.481808","article-title":"Resveratrol induces mitochondrial biogenesis and ameliorates Ang II-induced cardiac remodeling in transgenic rats harboring human renin and angiotensinogen genes","volume":"19","author":"Biala","year":"2010","journal-title":"Blood Press"},{"key":"2024103012143798600_CIT0038","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1089\/ars.2012.4777","article-title":"Mitochondrial dynamics in cardiovascular health and disease","volume":"19","author":"Ong","year":"2013","journal-title":"Antioxid Redox Signal"},{"key":"2024103012143798600_CIT0039","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1111\/bph.12516","article-title":"Mitochondrial fusion and fission proteins: novel therapeutic targets for combating cardiovascular disease","volume":"171","author":"Hall","year":"2014","journal-title":"Br J Pharmacol"}],"container-title":["Journal of Pharmacy and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jpp\/article-pdf\/73\/11\/1520\/60217387\/rgab124.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jpp\/article-pdf\/73\/11\/1520\/60217387\/rgab124.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T16:54:37Z","timestamp":1730307277000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jpp\/article\/73\/11\/1520\/6359181"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,1]]},"references-count":39,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11,1]]},"published-print":{"date-parts":[[2021,11,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jpp\/rgab124","relation":{},"ISSN":["0022-3573","2042-7158"],"issn-type":[{"value":"0022-3573","type":"print"},{"value":"2042-7158","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,11,1]]},"published":{"date-parts":[[2021,11,1]]}}}