Аннотация
AIMS: The Na$^+$/K$^+$-ATPase (NKA) alpha2-isoform is preferentially
located in the t-tubules of cardiomyocytes and is functionally coupled
to the Na$^+$/Ca(+-exchanger (NCX) and Ca$^2+$ regulation
through intracellular Na$^+$ concentration (Na$^+$i). We
hypothesized that downregulation of the NKA alpha2-isoform during
congestive heart failure (CHF) disturbs the link between Na$^+$
and Ca$^2+$, and thus the control of cardiomyocyte contraction.
METHODS AND RESULTS: NKA isoform and t-tubule distributions were
studied using immunocytochemistry, confocal and electron microscopy
in a post-infarction rat model of CHF. Sham-operated rats served
as controls. NKA and NCX currents (I NKA and I NCX) were measured
and alpha2-isoform current (I NKA,alpha2) was separated from total
I NKA using 0.3 microM ouabain. Detubulation of cardiomyocytes was
performed to assess the presence of alpha2-isoforms in the t-tubules.
In CHF, the t-tubule network had a disorganized appearance in both
isolated cardiomyocytes and fixed tissue. This was associated with
altered expression patterns of NKA alpha1- and alpha2-isoforms. I
NKA,alpha2 density was reduced by 78\% in CHF, in agreement with
decreased protein expression (74\%). When I NKA,alpha2 was blocked
in Sham cardiomyocytes, contractile parameters converged with those
observed in CHF. In Sham, abrupt activation of I NKA led to a decrease
in I NCX, presumably due to local depletion of Na$^+$i in the
vicinity of NCX. This decrease was smaller when the alpha2-isoform
was downregulated (CHF) or inhibited (ouabain), indicating that the
alpha2-isoform is necessary to modulate local Na$^+$i close
to NCX. CONCLUSION: Downregulation of the alpha2-isoform causes attenuated
control of NCX activity in CHF, reducing its capability to extrude
Ca$^2+$ from cardiomyocytes.
Пользователи данного ресурса
Пожалуйста,
войдите в систему, чтобы принять участие в дискуссии (добавить собственные рецензию, или комментарий)