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Abstract

Cardiomyocytes express several isoenzymes of protein kinase C (PKC), which as a group have been implicated in the induction of left ventricular hypertrophy (LVH) and its transition to heart failure. Individual PKC isoenzymes also require transphosphorylation and autophosphorylation for enzymatic activity. To determine whether PKC isoenzyme expression and autophosphorylation are altered during LVH progression in vivo, suprarenal abdominal aortic coarctation was performed in Sprague-Dawley rats. Quantitative Western blotting was performed on LV tissue 1, 8 and 24 weeks after aortic banding, using antibodies specific for total PKCalpha, PKCdelta and PKCepsilon, and their C-terminal autophosphorylation sites. Aortic banding produced sustained hypertension and gradually developing LVH that progressed to diastolic heart failure over time. PKCepsilon levels and autophosphorylation were not significantly different from sham-operated controls during any stage of LVH progression. PKCalpha expression levels were also unaffected during the induction of LVH, but increased 3.2 +/- 0.8 fold during the transition to heart failure. In addition, there was a high degree of correlation between PKCalpha levels and the degree of LVH in 24 week banded animals. However, autophosphorylated PKCalpha was not increased at any time point. In contrast, PKCdelta autophosphorylation was increased prior to the development of LVH, and also during the transition to heart failure. The increased PKCdelta autophosphorylation in 1 week banded rats was not accompanied by an increase in total PKCdelta, whereas total PKCdelta levels were markedly increased (6.0 +/- 1.7 fold) in 24 week banded animals. Furthermore, both phosphorylated and total PKCdelta levels were highly correlated with the degree of LVH in 24 week banded rats. In summary, we provide indirect evidence to indicate that PKCdelta may be involved in the induction of pressure overload LVH, whereas both PKCdelta and PKCalpha may be involved in the transition to heart failure.

Cardiomyocyte-specific expression of CRNK, the C-terminal domain of PYK2, maintains ventricular function and slows ventricular remodeling in a mouse model of dilated cardiomyopathy

“…LV PYK2 expression and activation were indeed markedly increased in caPKCε TG mice as compared to their nonTG littermates, suggesting a role for PYK2 in the pathogenesis of this and other forms of experimental and human LV remodeling and HF [1,12,31]. caPKCε expression in vivo resulted in progressive LV dysfunction, LV dilatation and wall thinning which was apparent at 3mo of age, and which progressed to overt HF and sudden death in older mice.…”

Independent modulation of contractile performance by cardiac troponin I Ser43 and Ser45 in the dynamic sarcomere

“…Regardless of the trigger, this signaling behavior appears to play a role in restoring contractile function back towards the original steady-state. An absence of this signaling response could accelerate the onset of end-stage heart failure when PKC activity [17-20,22] and cTnI S43/S45 phosphorylation [11-14,31,50] are elevated during periods of cardiac dysfunction.…”

Functional communication between PKC-targeted cardiac troponin I phosphorylation sites

“…Elevated protein kinase C (PKC) expression and activity is associated with cardiac dysfunction in human and animal models of heart failure (HF; (2,4,11)). One of the downstream targets for PKC is the thin filament molecular switch, cardiac troponin I (cTnI), which is phosphorylated at residues S23/24, S43/45 and T144 (29,34,35).…”