{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T19:24:23Z","timestamp":1783365863383,"version":"3.54.6"},"reference-count":50,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,4,7]],"date-time":"2020-04-07T00:00:00Z","timestamp":1586217600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rationale: Heart failure (HF) is marked by dampened cardiac contractility. A mild therapeutic target that improves contractile function without desensitizing the \u03b2-adrenergic system during HF may improve cardiac contractility and potentially survival. Inhibiting protein kinase C \u03b1 (PKC\u03b1) activity may fit the criteria of a therapeutic target with milder systemic effects that still boosts contractility in HF patients. PKC\u03b1 activity has been observed to increase during HF. This increase in PKC\u03b1 activity is perplexing because it is also accompanied by up-regulation of a molecular braking mechanism. Objective: I aim to explore how PKC\u03b1 activity can be increased and maintained during HF despite the presence of a molecular braking mechanism. Methods and Results: Using a computational approach, I show that the local diacylglycerol (DAG) signaling is regulated through a two-compartment signaling system in cardiomyocytes. These results imply that after massive myocardial infarction (MI), local homeostasis of DAG signaling is disrupted. The loss of this balance leads to prolonged activation of PKC\u03b1, a key molecular target linked to LV remodeling and dysfunctional filling and ejection in the mammalian heart. This study also proposes an explanation for how DAG homeostasis is regulated during normal systolic and diastolic cardiac function. Conclusions: I developed a novel two-compartment computational model for regulating DAG homeostasis during Ang II-induced heart failure. This model provides a promising tool with which to study mechanisms of DAG signaling regulation during heart failure. The model can also aid in identification of novel therapeutic targets with the aim of improving the quality of life for heart failure patients.<\/jats:p>","DOI":"10.3390\/ijms21072561","type":"journal-article","created":{"date-parts":[[2020,4,8]],"date-time":"2020-04-08T05:59:47Z","timestamp":1586325587000},"page":"2561","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Increase in PKC\u03b1 Activity during Heart Failure Despite the Stimulation of PKC\u03b1 Braking Mechanism"],"prefix":"10.3390","volume":"21","author":[{"given":"Naveed","family":"Aslam","sequence":"first","affiliation":[{"name":"BioSystOmics 4424 Jim West Street, Bellaire, TX 77401, USA"},{"name":"Department of Chemistry &amp; Chemical Engineering, Lahore University of Management Sciences (LUMS), Lahore 54792, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1093\/eurheartj\/14.suppl_A.33","article-title":"Cardiac dysfunction and development of heart failure","volume":"14","author":"Ertl","year":"1993","journal-title":"Eur. Heart J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1093\/cvr\/cvn333","article-title":"Myocardial repair\/remodelling following infarction: Roles of local factors","volume":"81","author":"Sun","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1161\/01.CIR.88.5.2267","article-title":"Effect of inotropic stimulation on the negative force-frequency relationship in the failing human heart","volume":"88","author":"Schwinger","year":"1993","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1097\/FJC.0b013e3181b2b6d4","article-title":"Neurohormonal regulation of cardiac ion channels in chronic heart failure","volume":"54","author":"Kurokawa","year":"2009","journal-title":"J. Cardiovasc. Pharm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.1161\/CIRCULATIONAHA.110.942268","article-title":"Molecular Pathways Underlying Cardiac Remodeling During Pathophysiological Stimulation","volume":"122","author":"Kehat","year":"2010","journal-title":"Circulation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1161\/CIRCRESAHA.113.301651","article-title":"Mechanisms of Altered Ca2+ Handling in Heart Failure","volume":"113","author":"Luo","year":"2013","journal-title":"Circ. Res."},{"key":"ref_7","unstructured":"Jarkko, P. (2002). Regulation of Cardiac Responses to Increased Load. Role of Endothelin-1, Angiotensin II and Collagen XV, Department of Pharmacology and Toxicology and Biocenter Oulu, University of Oulu, P.O.Box 5000, FIN-90014 University of Oulu, Finland."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1161\/CIRCRESAHA.109.195313","article-title":"Protein kinase C{alpha}, but not PKC{beta} or PKC{gamma}, regulates contractility and heart failure susceptibility: Implications for ruboxistaurin as a novel therapeutic approach","volume":"105","author":"Liu","year":"2009","journal-title":"Circ. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1161\/CIRCULATIONAHA.105.592550","article-title":"Pharmacological- and Gene Therapy-Based Inhibition of Protein Kinase C\u03b1\/\u03b2 Enhances Cardiac Contractility and Attenuates Heart Failure","volume":"114","author":"Michael","year":"2006","journal-title":"Circulation"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"H3768","DOI":"10.1152\/ajpheart.00486.2007","article-title":"Inducible and myocyte-specific inhibition of PKCalpha enhances cardiac contractility and protects against infarction-induced heart failure","volume":"293","author":"Hambleton","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1152\/physiol.00009.2012","article-title":"Cardiac Actions of Protein Kinase C Isoforms","volume":"27","author":"Steinberg","year":"2012","journal-title":"Physiology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1161\/01.RES.0000105087.79373.17","article-title":"Protein kinase C alpha negatively regulates systolic and diastolic function in pathological hypertrophy","volume":"93","author":"Hahn","year":"2003","journal-title":"Circ. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1161\/CIRCULATIONAHA.105.560771","article-title":"Cardiac-specific overexpression of diacylglycerol kinase zeta prevents Gq protein-coupled receptor agonist-induced cardiac hypertrophy in transgenic mice","volume":"113","author":"Arimoto","year":"2006","journal-title":"Circulation"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"H1105","DOI":"10.1152\/ajpheart.00927.2006","article-title":"Cardiac-specific overexpression of diacylglycerol kinase zeta attenuates left ventricular remodeling and improves survival after myocardial infarction","volume":"292","author":"Niizeki","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1253\/circj.71.276","article-title":"Diacylglycerol kinase zeta attenuates pressure overload-induced cardiac hypertrophy","volume":"71","author":"Harada","year":"2007","journal-title":"Circ. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"H245","DOI":"10.1152\/ajpheart.00066.2008","article-title":"Diacylglycerol kinase-epsilon restores cardiac dysfunction under chronic pressure overload: A new specific regulator of Galpha(q) signaling cascade","volume":"295","author":"Niizeki","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/S0898-6568(04)00056-7","article-title":"Diacylglycerol kinases","volume":"16","author":"Bai","year":"2004","journal-title":"Cell. Signal."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.pharmthera.2007.04.010","article-title":"Role of diacylglycerol kinase in cellular regulatory processes: A new regulator for cardiomyocyte hypertrophy","volume":"115","author":"Takeishi","year":"2007","journal-title":"Pharm. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1083\/jcb.200208120","article-title":"Association of diacylglycerol kinase zeta with protein kinase C alpha: Spatial regulation of diacylglycerol signaling","volume":"160","author":"Luo","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4406","DOI":"10.1091\/mbc.e11-03-0247","article-title":"Diacylglycerol kinase \u03b6 controls diacylglycerol metabolism at the immunological synapse","volume":"22","author":"Gharbi","year":"2011","journal-title":"Mol. Biol. Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"39542","DOI":"10.1074\/jbc.M307153200","article-title":"Protein Kinase C{alpha} Phosphorylates and Negatively Regulates Diacylglycerol Kinase {zeta}","volume":"278","author":"Luo","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"E395","DOI":"10.1152\/ajpendo.00477.2009","article-title":"Protein kinase C: Poised to signal","volume":"298","author":"Newton","year":"2010","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6300","DOI":"10.1074\/jbc.M707319200","article-title":"The phosphatase PHLPP controls the cellular levels of protein kinase C","volume":"283","author":"Gao","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1161\/01.CIR.0000111581.15521.F5","article-title":"Manipulating cardiac contractility in heart failure: Data from mice and men","volume":"109","author":"Dorn","year":"2004","journal-title":"Circulation"},{"key":"ref_25","first-page":"S14","article-title":"Pathophysiology of congestive heart failure","volume":"4","author":"Francis","year":"2003","journal-title":"Rev. Cardiovasc. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1161\/01.RES.0000060027.40275.A6","article-title":"Is depressed myocyte contractility centrally involved in heart failure?","volume":"92","author":"Houser","year":"2003","journal-title":"Circ. Res."},{"key":"ref_27","first-page":"I82","article-title":"Adrenergic inotropic responsiveness of patients with heart failure: Studies with intracoronary dobutamine infusion","volume":"61","author":"Colucci","year":"1987","journal-title":"Circ. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1056\/NEJM199307153290301","article-title":"Effects of vesnarinone on morbidity and mortality in patients with heart failure. Vesnarinone Study Group","volume":"329","author":"Feldman","year":"1993","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/S0025-7125(02)00185-2","article-title":"Role of nonglycosidic inotropic agents: Indications, ethics, and limitations","volume":"87","author":"Chatterjee","year":"2003","journal-title":"Med. Clin. N. Am."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1161\/01.CIR.0000078349.43742.8A","article-title":"Clinical use of inotropic therapy for heart failure: Looking backward or forward?","volume":"108","year":"2003","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1067\/mhj.2001.117606","article-title":"Inotropic therapy for heart failure: An evidence-based approach","volume":"142","author":"Felker","year":"2001","journal-title":"Am. Heart J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1056\/NEJM199307013290101","article-title":"Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting- enzyme inhibitors. Radiance Study","volume":"329","author":"Packer","year":"1993","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Digitalis Investigation Group (1993). The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N. Engl. J. Med., 336, 525\u2013533.","DOI":"10.1056\/NEJM199702203360801"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nm1000","article-title":"PKC-\u03b1 regulates cardiac contractility and propensity toward heart failure","volume":"10","author":"Braz","year":"2004","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"H26","DOI":"10.1152\/ajpheart.2000.279.1.H26","article-title":"Diacylglycerol and fatty acids synergistically increase cardiomyocyte contraction via activation of PKC","volume":"279","author":"Pi","year":"2000","journal-title":"Am. J. Phsiol. Heart Cir. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"E489","DOI":"10.1152\/ajpendo.00569.2010","article-title":"Cardiomyocyte lipids impair \u03b2-adrenergic receptor function via PKC activation","volume":"300","author":"Drosatos","year":"2011","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.abb.2003.08.020","article-title":"Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes","volume":"419","author":"Chavez","year":"2003","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1172\/JCI10947","article-title":"A novel mouse model of lipotoxic cardiomyopathy","volume":"107","author":"Chiu","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1091\/mbc.e05-08-0742","article-title":"A critical role for eukaryotic elongation factor 1A-1 in lipotoxic cell death","volume":"17","author":"Borradaile","year":"2006","journal-title":"Mol. Biol. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbamcr.2004.05.002","article-title":"Fatty acyl CoA-mediated inhibition of endoplasmic reticulum assembly","volume":"1693","author":"Turner","year":"2004","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.bbalip.2009.09.011","article-title":"Mitochondrial dysfunction and lipotoxicity","volume":"1801","author":"Schrauwen","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"50230","DOI":"10.1074\/jbc.M200958200","article-title":"Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle","volume":"277","author":"Yu","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1016\/j.lfs.2003.08.022","article-title":"Selective and transient activation of protein kinase C alpha by fumonisin B1, a ceramide synthase inhibitor mycotoxin, in cultured porcine renal cells","volume":"74","author":"Gopee","year":"2004","journal-title":"Life Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4499","DOI":"10.1091\/mbc.e03-03-0190","article-title":"Diacylglycerol kinase-zeta localization in skeletal muscle is regulated by phosphorylation and interaction with syntrophins","volume":"14","author":"Abramovici","year":"2003","journal-title":"Mol. Biol. Cell"},{"key":"ref_45","first-page":"2176","article-title":"Transient PKC\u03b1 shuttling to the immunological synapse is governed by Diacylglycerol kinase \u03b6 and regulates L-selection shedding","volume":"126","author":"Gharbi","year":"2013","journal-title":"J. Cell Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1161\/hh1501.094185","article-title":"Gene Expression and In Situ Localization of Diacylglycerol Kinase Isozymes in Normal and Infarcted Rat Hearts Effects of Captopril Treatment","volume":"89","author":"Takeda","year":"2001","journal-title":"Circ. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"26688","DOI":"10.1074\/jbc.M112.378588","article-title":"Activation of Transient Receptor Potential Canonical 3 (TRPC3)-mediated Ca+2 Entry by A1 Adenosine Receptor in Cardiomyocytes Disturbs Atrioventricular Conduction","volume":"287","author":"Sabourin","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1161\/01.RES.73.3.424","article-title":"Signal Transduction Pathways of Angiotensin-II Induced c-fos Gene Expression in Cardiac Myocytes In-Vitro Roles of Phospholipid-Derived Second Messengers","volume":"73","author":"Sadoshima","year":"1993","journal-title":"Circ. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/29337","article-title":"Protein kinase C regulates the nuclear localization of diacylglycerol kinase-Zeta","volume":"394","author":"Topham","year":"1998","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"11196","DOI":"10.1073\/pnas.93.20.11196","article-title":"A 104-kDa diacylglycerol kinase containing ankyrin-like repeats localizes in the cell nucleus","volume":"93","author":"Goto","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/7\/2561\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:16:15Z","timestamp":1760174175000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/7\/2561"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,7]]},"references-count":50,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["ijms21072561"],"URL":"https:\/\/doi.org\/10.3390\/ijms21072561","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,7]]}}}