22 research outputs found
Single acute stress-induced progesterone and ovariectomy alter cardiomyocyte contractile function in female rats
Aim To assess how ovarian-derived sex hormones (in particular
progesterone) modify the effects of single acute
stress on the mechanical and biochemical properties of
left ventricular cardiomyocytes in the rat.
Methods Non-ovariectomized (control, n = 8) and ovariectomized
(OVX, n = 8) female rats were kept under normal
conditions or were exposed to stress (control-S, n = 8
and OVX-S, n = 8). Serum progesterone levels were measured
using a chemiluminescent immunoassay. Left ventricular
myocardial samples were used for isometric force
measurements and protein analysis. Ca2+-dependent active
force (Factive), Ca2+-independent passive force (Fpassive),
and Ca2+-sensitivity of force production were determined
in single, mechanically isolated, permeabilized cardiomyocytes.
Stress- and ovariectomy-induced alterations in myofilament
proteins (myosin-binding protein C [MyBP-C], troponin
I [TnI], and titin) were analyzed by sodium dodecyl
sulfate gel electrophoresis using protein and phosphoprotein
stainings. Results Serum progesterone levels were significantly increased
in stressed rats (control-S, 35.6 ± 4.8 ng/mL and
OVX-S, 21.9 ± 4.0 ng/mL) compared to control (10 ± 2.9
ng/mL) and OVX (2.8 ± 0.5 ng/mL) groups. Factive was higher
in the OVX groups (OVX, 25.9 ± 3.4 kN/m2 and OVX-S,
26.3 ± 3.0 kN/m2) than in control groups (control, 16.4 ± 1.2
kN/m2 and control-S, 14.4 ± 0.9 kN/m2). Regarding the
potential molecular mechanisms, Factive correlated with
MyBP-C phosphorylation, while myofilament Ca2+-sensitivity
inversely correlated with serum progesterone levels
when the mean values were plotted for all animal groups.
Fpassive was unaffected by any treatment.
Conclusion Stress increases ovary-independent synthesis
and release of progesterone, which may regulate Ca2+-sensitivity
of force production in left ventricular cardiomyocytes.
Stress and female hormones differently alter Ca2+-
dependent cardiomyocyte contractile force production,
which may have pathophysiological importance during
stress conditions affecting postmenopausal women
Long-Term PDE-5A Inhibition Improves Myofilament Function in Left and Right Ventricular Cardiomyocytes through Partially Different Mechanisms in Diabetic Rat Hearts
Heart failure with preserved ejection fraction (HFpEF) and right ventricular (RV) dysfunc-
tion are frequent complications of diabetic cardiomyopathy. Here we aimed to characterize RV and
left ventricular (LV) remodeling and its prevention by vardenafil (a long-acting phosphodiesterase-
5A (PDE-5A) inhibitor) administration in a diabetic HFpEF model. Zucker Diabetic Fatty (ZDF)
and control, ZDF Lean (Lean) male rats received 10 mg/kg vardenafil (ZDF + Vard; Lean + Vard)
per os, on a daily basis for a period of 25 weeks. In vitro force measurements, biochemical and
histochemical assays were employed to assess cardiomyocyte function and signaling. Vardenafil
treatment increased cyclic guanosine monophosphate (cGMP) levels and decreased 3-nitrotyrosine
(3-NT) levels in the left and right ventricles of ZDF animals, but not in Lean animals. Cardiomyocyte
passive tension (Fpassive) was higher in LV and RV cardiomyocytes of ZDF rats than in those receiving
preventive vardenafil treatment. Levels of overall titin phosphorylation did not differ in the four
experimental groups. Maximal Ca2+-activated force (Fmax) of LV and RV cardiomyocytes were
preserved in ZDF animals. Ca2+-sensitivity of isometric force production (pCa50) was significantly
higher in LV (but not in RV) cardiomyocytes of ZDF rats than in their counterparts in the Lean or Lean
+ Vard groups. In accordance, the phosphorylation levels of cardiac troponin I (cTnI) and myosin
binding protein-C (cMyBP-C) were lower in LV (but not in RV) cardiomyocytes of ZDF animals than
in their counterparts of the Lean or Lean + Vard groups. Vardenafil treatment normalized pCa50
values in LV cardiomyocytes, and it decreased pCa50 below control levels in RV cardiomyocytes in
the ZDF + Vard group. Our data illustrate partially overlapping myofilament protein alterations
for LV and RV cardiomyocytes in diabetic rat hearts upon long-term PDE-5A inhibition. While
uniform patterns in cGMP, 3-NT and Fpassive levels predict identical effects of vardenafil therapy
for the diastolic function in both ventricles, the uneven cTnI, cMyBP-C phosphorylation levels and
pCa50 values implicate different responses for the systolic function
Poly(ADP-ribose) polymerase-2 is a lipid-modulated modulator of muscular lipid homeostasis
There is a growing body of evidence that poly(ADP-ribose) polymerase-2 (PARP2), although originally described as a DNA repair protein, has a widespread role as a metabolic regulator. We show that the ablation of PARP2 induced characteristic changes in the lipidome. The silencing of PARP2 induced the expression of sterol regulatory element-binding protein-1 and -2 and initiated de novo cholesterol biosynthesis in skeletal muscle. Increased muscular cholesterol was shunted to muscular biosynthesis of dihydrotestosterone, an anabolic steroid. Thus, skeletal muscle fibers in PARP2(-/-) mice were stronger compared to those of their wild-type littermates. In addition, we detected changes in the dynamics of the cell membrane, suggesting that lipidome changes also affect the biophysical characteristics of the cell membrane. In in silico and wet chemistry studies, we identified lipid species that can decrease the expression of PARP2 and potentially phenocopy the genetic abruption of PARP2, including artificial steroids. In view of these observations, we propose a new role for PARP2 as a lipid-modulated regulator of lipid metabolism