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Cardiac Calcium
| Question | Answer |
|---|---|
| Backs et al 2006 | CaMKII phosphorylates histone deacetylase 4, restricting it to the cytoplasm by incr export and decr import. Depresses genes targeted by HDAC4 and promotes hypertrophy. CaMKII requires autophosphorylation which only occurs after a prolonged Ca rise. |
| Bernardo et al 2010 | Review: Concentric hypertrophy involves parallel addition of sarcomeres, pathological. Increased systolic wall stress causes path hypertrophy, increased venous return causes eccentric hypertrophy. IGF1R upreg in cardiac tissue mimicked exercise benefits. |
| Bers 2002 (only author) | Review: Ca binds troponn C to initiate contraction. Acidosis, phosphate and Mg reduce sensitivity to Ca, these rise in ischaemia to lower cardiac demands. Ca from associated RyRs shuts off CaL currents early. Phospholamban inhibits SR Ca ATPase |
| Carè et al 2007 | miR-133 and miR-1 are downregulated in hypertrophy. Overexpression inhibited hypertrophy. 3 models of hypertrophy (path and phys) all showed downreg of both. Inhibiting endogenous miR-133 and 1 caused hypertrophy. |
| Ceylan-Isik et al 2013 | Specific deletion of endothelin A receptor in cardiac tissue, increased survival in mice. Reduced the age-associated incr in wall thickness and reduced markers of pathological hypertrophy. SERCA and phospholamban less downregulated (reduced in aging) |
| Marx et al 2000 (led by Marks) | Widely discredited. Calculated level of RyR phosphorylation by immunoprecipitating then adding labelled phosphate to saturate, saw hyperphosphorylation in failing hearts. Pretreatment with PKA reduced Co-IP of RyRs with FKBP12.6. |
| Guo et al 2010 | Discredits Marx, FKBP12.6 inhibits RyR but only bound to 20% (low expression high affinity). Activation with PKA had no effect on FKBP binding, incr spark freq due to phospholamban effects. Backs up numerous papers unable to repeat Marx 2000 (Houser 2010) |
| Kedzierski et al 2003 | Cardiomyocyte specific ETA receptor KO, 78% knockdown in mRNA. Normal hypertrophy and contraction to AT-II and isoproterenol. ETB levels double normal, probably compensating. |
| McDonough & Glembotski 1992 | ANF mRNA increased on electrical stimulation of cultured myocytes. Nifedipine and CaM blocker attenuated this rise so appears to be calcium influx signalling via calmodulin. mRNA increased, may be an indirect function of the miRNAs from Care et al 2007 |
| Molkentin 2006 (only author) | Review: Cardiac calcium sources are CaL, CaT (only immature/hypertrophied myocytes), TRPC, IP3R (probably Orai too). HDAC5 seems to be involved, moves to the nucleus, blockable by IP3R anatagonist not reproducible by inducing cytosolic Ca fluxes. |
| Nakayama et al 2010 | IP3R2 upregulation led to hypertrophy. Similarly expression of an IP3 sponge decreased the hypertrophic response to several stimuli (isoprenaline/angiotensin) although aortic banding still caused it. Increasing IP3R expression increased NFAT activity |
| Wu et al 2006 | HDAC5 phosphorylation and nuclear export allows transcription of MEF2 and hypertrophy. CaM blocker blocked response but global Ca rise didnt trigger until v. high (local signal). Blockers showed PKD & CaMKII did 50% each. ET-1 and IP3r invovled (blockers) |
| Van Berlo et al 2013 | Review: Therapies. GRK2 inh in trials, viral vector, slows hypertrophy in response to isoproterenol. Biased antag vs AT-R is in trials, inh G-prot response, retains beta-arrestin. TRPc modulation may be good, promising due to progress with TRPm and TRPV |
| Waring et al 2012 | Rate of death necessitates cardiac cell replacement, study shows treadmill exercise induces myocyte division. Uses BrdU (amount of labelling corresponds with training intensity). Ki67 used to label dividing cells, more in trained animals. Incr Stem cells |
| Wang et al 2001 | Local Ca influx through L-type Ca channels (sparklet) allows activation of 4-6 RyRs. used confocal line scanning. Cell-attached patch clamping to isolate single channels. Sparklets blockable by nifedipine but not ryanodine (which blocks RyRs) |
| Mackenzie et al 2004 | Used confocal linescan to show that calcium influxes in atrial myocytes are limited to the cell's periphery by SERCA & mitochondrial buffering. Global Ca rise req'd incr extracell Ca, RyRs sensitised (w/ caffeine), SERCA blocked or mitochondria uncoupled |
| Davies et al 1996 | Used explanted heart tissue. Myocytes isolated. Reduced calcium increase in response to beta agonists in older hearts. Consistent with reduced number of BetaARs. shows reduced post-synaptic response, may also be pre-syn changes |
| Ungerer et al 1993 | Increased beta-adrenoceptor kinase in failing hearts. Incr mRNA and activity. |
| Gwathmey et al 1987 | calcium handling altered in heart failure, used tissue taken from explanted hearts. Prolonged calcium transient with slower rise and fall in tension. Slower to contract and slower to relax. |
| Kubalova et al 2005 | Impaired calcium handling in chronic heart failure. Prolonged Ca transient of lower amplitude. RyR sensitivity increased but protein levels greatly reduced. |
| Drawnel et al 2012 | Activation of IP3Rs leads to a downregulation of MiR-133, which disinhibits expression of the IP3R gene, generating positive feedback. miR-133 measured by qPCR. |
| Zhang et al 2013 | PLCε is involved in hypertrophic response to ET-1. KO mice show reduced hypertrophy post-aortic banding. Thought to increase PKD activity via PKCε, PKD then phosphorylates HDACs. PLC, PKC and PKD anchored together by an AKAP. |
| Mahmoud et al 2013 | Deletion of Meis1 caused prolonged proliferation in mouse hearts post-natally. Conditional deletion caused the same increase in myocyte proliferation. KO mice had increased mitosis well into adulthood (BrdU) with normal cardiac function. |
| Zima et al 2013 | Mitochondrial depolarisation by protonophore caused transient prevention of Ca rises, thought to be due to H+ & Mg inh RyR. This recovered over time, & Ca transients were eventually enhanced due to decr buffering & decr extrusion (loss of Na grad for NCX) |
Created by:
Jonmassie
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