Increased myocardial stiffness with maintenance of length-dependent calcium activation by female sex hormones in diabetic rats

Bupha-Intr, Tepmanas; Oo, Ye Win; Wattanapermpool, Jonggonnee

doi:10.1152/ajpheart.00411.2010

Cited by 25 publications

(30 citation statements)

References 46 publications

(61 reference statements)

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“…This finding is consistent with an earlier report demonstrating unchanged passive stiffness in OVX animals (56). No differences were found in the phosphorylation of myofilament proteins between the control and control-S groups.…”

Section: Discussionsupporting

confidence: 94%

Single acute stress-induced progesterone and ovariectomy alter cardiomyocyte contractile function in female rats

et al. 2014

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AimTo 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.MethodsNon-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.ResultsSerum 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.

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Section: Discussionsupporting

confidence: 94%

Single acute stress-induced progesterone and ovariectomy alter cardiomyocyte contractile function in female rats

et al. 2014

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“…Consistent with previous studies [20, 21], the present experiments demonstrated that isometric force and passive stiffness values measured in pCa 9.0 solutions with minimal free Ca 2+ did not differ between the CTRL and STZ groups at physiological sarcomere lengths (p>0.05 for STZ, sex and interaction, Linear Mixed Model, Table 3). SDS-VAGE gels [17] did however show a small but statistically significant reduction in the proportion of titin found as the ‘stiff’ N2B isoform (molecular weight ~2.97 MDa) in the STZ samples (2 way ANOVA, p<0.008, STZ).…”

Section: Resultssupporting

confidence: 92%

“…The percentage of titin expressed as the larger N2BA isoform, N2BA-A1 (~3.39 MDa) was increased in the STZ animals while the relative content of the smaller N2BA-A2 isoform (~3.22 MDa) was decreased (Table 5) [22]. Myocardial collagen content was not measured in this work but others [21] have shown that it could be increased by streptozotocin injection at 6 weeks.…”

Section: Resultsmentioning

confidence: 77%

“…We also note that total STZ treatment did not change passive stiffness (Table 3). Although we did not measure collagen content in this work, Bupha-Intr et al [21] have shown that it is increased 6 weeks after STZ injection in this animal model, potentially compensating for the reduced titin stiffness. These data support the finding that the elastic limit rather than passive stiffness drives the changes in short range force.…”

Section: Discussionmentioning

confidence: 80%

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Increased myocardial short-range forces in a rodent model of diabetes reflect elevated content of β myosin heavy chain

Chung

Mitov

Callahan

et al. 2014

Archives of Biochemistry and Biophysics

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Diastolic dysfunction is a clinically significant problem for patients with diabetes and often reflects increased ventricular stiffness. Attached cross-bridges contribute to myocardial stiffness and produce short-range forces, but it is not yet known whether these forces are altered in diabetes. In this study, we tested the hypothesis that cross-bridge-based short-range forces are increased in the streptozotocin (STZ) induced rat model of Type 1 diabetes. Chemically permeabilized myocardial preparations were obtained from 12 week old rats that had been injected with STZ or vehicle 4 weeks earlier, and activated in solutions with pCa (=−log10[Ca2+]) values ranging from 9.0 to 4.5. The short-range forces elicited by controlled length changes were ~67% greater in the samples from the diabetic rats than in the control preparations. This change was mostly due to an increased elastic limit (the length change at the peak short-range force) as opposed to increased passive muscle stiffness. The STZ-induced increase in short-ranges forces is thus unlikely to reflect changes to titin and/or collagen filaments. Gel electrophoresis showed that STZ increased the relative expression of β myosin heavy chain. This molecular mechanism can explain the increased short-ranges forces observed in the diabetic tissue if β myosin molecules remain bound between the filaments for longer durations than α molecules during imposed movements. These results suggest that interventions that decrease myosin attachment times may be useful treatments for diastolic dysfunction associated with diabetes.

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“…Furthermore, as oxidative stress has been shown to reduce myofilament Ca 2+ sensitivity in the heart [59], it is possible that an increase in production of ROS leads to the decrease in myofilament Ca 2+ sensitivity observed in our study. On the other hand, previous studies have reported that short-term (10 weeks) OVX increases myofilament Ca 2+ sensitivity [60], so prolonged ovarian estrogen withdrawal may be required to desensitize myofilaments in the aging female heart. ROS also reduces SERCA2 activity, which is not compatible with the faster time courses of contraction and Ca 2+ transients observed in our study [58,61].…”

Section: Discussionmentioning

confidence: 99%

The Impact of Ovariectomy on Calcium Homeostasis and Myofilament Calcium Sensitivity in the Aging Mouse Heart

et al. 2013

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This study determined whether deficiency of ovarian estrogen starting very early in life promoted age-associated Ca2+ dysregulation and contractile dysfunction in isolated ventricular myocytes. Myocytes were isolated from anesthetized C57BL/6 female mice. Animals received an ovariectomy or sham-operation at one month and were aged to ~24 months. Excitation-contraction coupling parameters were compared in fura-2 loaded myocytes (37°C). While Ca2+ transients were larger and faster in field-stimulated myocytes from ovariectomized mice, ovariectomy had no effect on peak fractional shortening. Similarly, ovariectomy had no effect on fractional shortening measured in vivo by echocardiography (values were 60.5 ± 2.9 vs. 60.3 ± 2.5% in sham and ovariectomized, respectively; n=5 mice/group). Ovariectomy did decrease myofilament Ca2+ sensitivity, as evidenced by a 26% increase in the Ca2+ required to activate actomyosin MgATPase in ovariectomized hearts. Larger Ca2+ transients were attributable to a 48% increase in peak Ca2+ current, along with an increase in the amplitude, width and frequency of Ca2+ sparks measured in fluo-4 loaded myocytes. These changes in Ca2+ handling were not due to increased expression of Ca2+ channels (Cav1.2), sarcoplasmic reticulum Ca2+ ATPase (SERCA2) or Na+-Ca2+ exchanger in ovariectomized hearts. However, ovariectomy increased sarcoplasmic reticulum Ca2+ stores by ~90% and promoted spontaneous Ca2+ release from the sarcoplasmic reticulum when compared to sham controls. These observations demonstrate that long-term ovariectomy promotes intracellular Ca2+ dysregulation, reduces myofilament Ca2+ sensitivity and increases spontaneous Ca2+ release in the aging female heart.

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Increased myocardial stiffness with maintenance of length-dependent calcium activation by female sex hormones in diabetic rats

Cited by 25 publications

References 46 publications

Single acute stress-induced progesterone and ovariectomy alter cardiomyocyte contractile function in female rats

Single acute stress-induced progesterone and ovariectomy alter cardiomyocyte contractile function in female rats

Increased myocardial short-range forces in a rodent model of diabetes reflect elevated content of β myosin heavy chain

The Impact of Ovariectomy on Calcium Homeostasis and Myofilament Calcium Sensitivity in the Aging Mouse Heart

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