Multifarious molecular signaling cascades of cardiac hypertrophy: can the muddy waters be cleared?
The mammalian heart during its development and in response to physiological or pathological stimuli undergoes hypertrophic enlargement, a consequence of an increase in cardiac myocyte size. Cardiac hypertrophy in response to biomechanical stress stimuli may be initially a compensatory event, but gradually becomes a pathological event if the mechanical stress on the myocardium persists. In fact, studies have shown cardiac hypertrophy as a dominant risk factor for the development of heart failure and coronary artery disease. A number of complex signaling cascades were identified that regulate the cardiac hypertrophic response. Much progress has been made previously in identifying various target sites and understanding the molecular and cellular processes that are involved in the development of cardiac hypertrophy and heart failure. This has led drug discovery research in developing effective therapies to treat various cardiovascular diseases. However, the available therapeutic agents for the treatment of heart failure have limited effectiveness in halting the progression of the disease. Therefore, novel therapeutic strategies are being identified to inhibit the development of cardiac hypertrophy before heart failure develops. In this review, we describe multifarious molecular signaling mechanisms involved in the pathogenesis of cardiac hypertrophy, including tumor necrosis factor-α, Wnt/Frizzled signals, calcineurin, mitofusin-2, mitogen-activated protein kinases, Janus kinase, Rho kinase, poly (ADP-ribose) polymerase, transcription factors, oxidative signals and G-protein-coupled-receptor-associated signaling system. Elucidation of signaling cascades that initiate cardiac hypertrophy will open up a new area of research in developing innovative therapeutics for the treatment of pathological cardiac hypertrophy.
Balakumar
Pitchai
P
Department of Pharmacology, SB College of Pharmacy, Sivakasi 626 130, India. pbala2006@gmail.com
Jagadeesh
Gowraganahalli
G
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D006332:Cardiomegaly / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D065095:Calcineurin Inhibitors; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000246:Adenosine Diphosphate Ribose; D020928:Mitogen-Activated Protein Kinases; D019703:Calcineurin