Troponin I phosphorylation in the normal and failing adult human heart.
BACKGROUND
In the failing human heart myofibrillar calcium sensitivity of tension development is greater and maximal myofibrillar ATPase activity is less than in the normal heart. Phosphorylation of the cardiac troponin I (cTnI)-specific NH2-terminus decreases myofilament sensitivity to calcium, while phosphorylation of other cTnI sites decreases maximal myofibrillar ATPase activity.


RESULTS
We examined cTnI phosphorylation in left ventricular myocardium collected from failing hearts at the time of transplant (n=20) and normal hearts from trauma victims (n=24). The relative amounts of actin, tropomyosin, and TnI did not differ between failing and normal myocardium. Using Western blot analysis with a monoclonal antibody (MAb) that recognizes the striated muscle TnI isoforms, we confirmed that the adult human heart expresses only cTnI. A cTnI-specific MAb recognized two bands of cTnI, designated cTnI1 and cTnI2, while a MAb whose epitope is located in the cTnI-specific NH2-terminus recognized only cTnI1. Alkaline phosphatase decreased the relative amount of cTnl1, while protein kinase A and protein kinase C increased cTnI1. The percentage of cTnI made up of cTnI1, the phosphorylated form of TnI, is greater in the normal than the failing human heart (P<.00).


CONCLUSIONS
This phosphorylation difference could underlie the reported greater myofibrillar calcium sensitivity of failing myocardium. The functional consequence of this difference may be an adaptive or maladaptive response to the lower and longer calcium concentration transient of the failing heart, eg, enhancing force development or producing ventricular diastolic dysfunction.
Bodor
G S
GS
Department of Laboratories, Denver Health Medical Center, Colo, USA.
Oakeley
A E
AE
Allen
P D
PD
Crimmins
D L
DL
Ladenson
J H
JH
Anderson
P A
PA
D000199:Actins / Q000378:metabolism; D000328:Adult; D000469:Alkaline Phosphatase / Q000494:pharmacology; D002303:Cardiac Output, Low / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology; D005333:Fetus / Q000378:metabolism; D006352:Heart Ventricles; D006801:Humans; D007536:Isomerism; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000494:pharmacology; D012016:Reference Values; D014335:Tropomyosin / Q000378:metabolism; D019210:Troponin I / Q000378:metabolism*
D000199:Actins; D014335:Tropomyosin; D019210:Troponin I; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D000469:Alkaline Phosphatase