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Cardiovascular Research 2005 66(2):318-323; doi:10.1016/j.cardiores.2004.06.028
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Copyright © 2004, European Society of Cardiology

In vivo gene transfer of parvalbumin improves diastolic function in aged rat hearts

Ulrich Schmidta, Xinsheng Zhua, Djamel Lebecheb, Fawzia Huqb, J. Luis Guerrerob and Roger J. Hajjarb,*

aDepartment of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
bCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, United States

* Corresponding author. Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, MA 02129, United States. Tel.: +1 617 726 3748; fax: +1 617 724 5806. Email address: rhajjar{at}partners.org

Received 12 April 2004; revised 25 June 2004; accepted 29 June 2004


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: Diastolic dysfunction is a characteristic finding of the aged mammalian heart. Parvalbumin acts as a Ca2+ sink and enhances relaxation in skeletal muscle, and overexpression of parvalbumin in myocardium increased cardiac relaxation in vitro as well as in vivo. Therefore, the objective of this study is to test the hypothesis that in vivo gene transfer of parvalbumin will improve diastolic dysfunction in aged rat heart.

Methods: We used adenovirus to transfer parvalbumin into two different rat models of aging: the Fischer 344 (F344) and the Fischer 344 x Brown Norway F1 hybrid (F344 x BN). Cardiac function was measured and compared after gene transfer.

Results: In vivo overexpression of parvalbumin in both rat aging models had no effect on systolic parameters but reduced left ventricular diastolic pressure and the time course of pressure decline. Overexpression of parvalbumin also improved the force frequency relationship in senescent rats.

Conclusion: In vivo overexpression of parvalbumin improves diastolic dysfunction in two rat models of senescence, and this effect is independent of the rat strain investigated. The results show promise that gene therapy of parvalbumin may address the impaired Ca2+ homeostasis and diastolic dysfunction without an increase in energy expenditure.

KEYWORDS Gene transfer; Aging; Contractile function; Hemodynamics


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Heart failure represents one of the major causes of morbidity and mortality in the elderly population [1,2]. Diastolic dysfunction is a characteristic finding of the aged mammalian heart [3–6]. About 40% of elderly with symptoms of congestive heart failure have normal ejection fraction but diastolic dysfunction [2,7]. In mammalians, the release and uptake of Ca2+ into the sarcoplasmic reticulum is one of the major components that control heart relaxation. Consequently, a decrease of SR Ca2+-ATPase pumps and function resulting in diastolic dysfunction has been reported in the aging heart [8–10]. The severity of diastolic dysfunction and specific mechanism of functional abnormalities may be related to the rat strain investigated [11,12]. Recently, it has been reported that adenoviral gene transfer of SR Ca2+-ATPase restored diastolic dysfunction in aged rat hearts [13]. This is, however, an energy-dependent approach. Depletion of energy resources is an import abnormality of failing myocardium [14,15]. In contrast, parvalbumin has been shown to increase relaxation through an ATP-independent mechanism. Due to its Ca2+ affinity, parvalbumin acts as a Ca2+ sink and enhances relaxation in skeletal muscle [16,17]. The protein is absent in cardiac tissue [18]. Overexpression of parvalbumin into normal adult myocardium increased cardiac relaxation in vitro [19] as well as in vivo [20] in normal hearts.

Because diastolic dysfunction is a hallmark of aging heart, the present study aimed to test the hypothesis that in vivo gene transfer of parvalbumin will improve or correct the diastolic dysfunction in two distinctly different rat models of aging:

(1) The Fischer 344 (F344) and
(2) The Fischer 344 x Brown Norway F1 hybrid (F344 x BN).


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Construction of recombinant adenoviruses
Two first-generation type 5 recombinant adenoviruses were used in these studies: Ad.β-galGFP and Ad.Parvalbumin. The construction of Ad.Parvalbumin has been described earlier and the recombinant viruses were prepared as high titer stocks by propagation in 293 cells [21,22]. The titer of stocks used for these studies were: 9 x 1010 pfu/ml for Ad.β-galGFP and 10 x 1011 pfu/ml for Ad.Parvalbumin with a particle/pfu ratio of 25:1 and 40:1, respectively. The viral particles/ml was determined using the following relationship: 1 unit of OD260=1012 viral particles/ml.

2.2. Experimental protocol
All animal experiments in this study were performed with the approval of the Animal Care Committee of Massachusetts General Hospital and in accordance with the National Institute of Health's Guide for the Care and Use of Laboratory Animals. 26- (aged) and 6-month-old (adult) male F344 and F344 x BN rats, respectively, obtained from the National Aging Institute were used in this study. Animals of both rat strains were divided into four groups:

(1) six uninfected, sham-operated aged rats;
(2) six aged rats infected with 1010 pfu Ad.β-galGFP;
(3) six aged rats infected with 1010 pfu Ad.Parvalbumin; and
(4) six uninfected sham-operated adult rats.

2.3. Adenoviral delivery protocol
The delivery of adenovirus has been described previously by our group in detail [22]. Briefly, rats were anesthetized with intraperitoneal (i.p.) pentobarbital (60 mg/kg) and then placed on a ventilator. The chest was entered from the left side through the third intercostal space. A 22-G catheter containing 200 µl of adenovirus was advanced from the apex of the left ventricle (LV) to the aortic root. The aorta and pulmonary arteries were clamped distal to the site of the catheter and the solution injected. The clamp was maintained for 10 s while the heart pumped against a closed system (isovolumically). After 10 s, the clamp on the aorta and pulmonary artery was released, the chest was closed, animals were extubated, and transferred back to their cages.

2.4. Pressure measurements
After adenovirus gene delivery, the protein expression usually reaches peak at day 2 and lasts for 7–10 days. Therefore, we measured the effects of overexpression of parvalbumin 48 h after gene delivery. Forty-eight hours after adenovirus gene transfer, rats in the different treatment groups were anesthetized with 60 mg/kg of pentobarbital and were then mechanically ventilated. The chest was then opened and a 1.8-F high-fidelity pressure transducer (MILAR Instruments, TX) introduced into the left ventricle. Left ventricular systolic pressure (LVSP), end-diastolic pressure (LVEDP), the maximal rates of pressure rise (+dP/dt) and of pressure fall (–dP/dt), and the time constant of isovolumic relaxation ({tau}) were measured or derived in the different groups. The time course of isovolumic relaxation was measured using the equation: P=P0e–t/{tau}+PB, where P is the left ventricular isovolumic pressure, P0 is pressure at the time of peak –dP/dt and PB is residual pressure. For over-pacing studies, a pair of electrodes for atrial pacing was placed at the left atria appendage, and force–frequency relationship was evaluated during stepwise increments of +50, +100, +150 and +200 bpm from the baseline.

2.5. Western blot analysis
Forty-eight hours after adenovirus gene transfer, we isolated membranes from the left ventricles of hearts as described earlier [22]. Briefly, left ventricular myocardium was suspended in a buffer containing 300 mmol/l sucrose, 1 mmol/l PMSF, 20 mmol/l PIPES at pH 7.4, homogenized and then centrifuged at 25,000 x g for 60 min and the pellet was resuspended in a buffer containing 600 mmol/l KCl, 30 mmol/l sucrose, 20 mmol/l PIPES, frozen in liquid nitrogen and stored at –70 °C. Protein concentrations were determined by Brad-ford Method (Bio-Rad). SDS-PAGE was performed under reducing conditions on a 7.5% separation gel. For immunoreactions, the blots were incubated with 1:2500 diluted monoclonal antibodies to parvalbumin, SERCA, Na+–Ca2+ exchanger (NCX) or anti-cardiac phospholamban (PLB) monoclonal IgG for 90 min at room temperature.

2.6. Statistical analysis
All values are presented as mean ± S.D. ANOVA was used to calculate statistical differences among the different groups and ANOVA for repeated measures was used where appropriate. Statistical significance was accepted at the level of p<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Quantification of calcium regulatory proteins
Adenoviral gene transfer of Ad.Parvalbumin induced a significant increase in parvalbumin content in 26-month-old F344 and F 344 x BN rats. The protein content of SERCA was significantly decreased in aged hearts of both strains, whereas the expression of phospholamban remained unchanged in the aged hearts. Overexpression of parvalbumin did not affect the expression of either SERCA, NCX or phospholamban (Fig. 1).


Figure 1
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  		Fig. 1 Determination of protein levels of parvalbumin, Na+–Ca2+ exchanger (NCX), SERCA and phospholamban (PLB). (A) Representative Western blots of SERCA, phospholamban, Na+–Ca2+ exchanger and parvalbumin, from crude membranes of left ventricles from adult uninfected Fisher 344 x BN rat hearts (n=6), preparations from aged uninfected Fisher 344 x BN rat hearts (n=6), preparations of aged hearts infected with ad.β-galGFP at day 2 (n=6), and preparations of aged Fisher 344 x BN hearts infected with Ad.Parvalbumin at day 2 (n=6). (B) Normalized densities of different bands of SERCA2a, PLB, NCX and parvalbumin. The density of bands was indicated using an arbitrary unit (AU). *Significant difference compared to the adults (p<0.05).

 
3.2. Hemodynamic effects of parvalbumin overexpression in aged hearts
As shown in Fig. 2 the systolic parameters were not altered in the aged rat hearts when compared to adult hearts. There was no difference between F344 and F344 x BN rats. Overexpression of parvalbumin did not change the left ventricular systolic pressures or rate of rise in pressure in both strains (Fig. 2). Diastolic parameters were significantly altered in both the aged rat hearts F344 and F344 x BN, as evidenced by a decrease in the maximal rate of decline of left ventricular pressure, an increase in diastolic pressure and a significantly prolonged time course of pressure decline ({tau}) as shown in Fig. 3. Overexpression of parvalbumin increased the maximal rate of decline of left ventricular systolic pressure in both aged rat strains and the time course of pressure decline ({tau}). In addition, it decreased diastolic pressure. We also monitored the basal heart rates in each group in this and the force–frequency relationship studies described below. No significant differences were observed in basal heart rates in each group (Table 1).


Figure 2
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  		Fig. 2 Measurements of systolic parameters. (A) Left ventricular systolic pressure and (B) +dP/dt in adult uninfected Fisher 344 and Fisher 344 x BN rat hearts (both n=6), aged uninfected rat Fisher 344 (n=6) and Fisher 344 x BN hearts (both n=6), aged Fisher 344 and Fisher 344 x BN hearts (both n=6) infected with Ad.β-galGFP at day 2 and aged Fisher 344 and Fisher 344 x BN (both n=6) hearts infected with Ad.Parvalbumin at day 2. Filled, adult; vertical lines, aged; dots, aged+β-gal; no fill, aged+Parvalbumin. No significant differences were observed in different groups. Heart rates for each group are shown in Table 1.

 

Figure 3
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  		Fig. 3 Measurements of diastolic parameters. (A) Diastolic pressure, (B) –dP/dt and (C) {tau} in adult uninfected Fisher 344 and Fisher 344 x BN rat hearts (both n=6), aged uninfected rat Fisher 344 and Fisher 344 x BN hearts (both n=6), aged Fisher 344 and Fisher 344 x BN hearts infected with Ad.β-galGFP at day 2 (both n=6) and aged Fisher 344 and Fisher 344 x BN hearts infected with Ad.Parvalbumin at day 2 (both n=6). Filled, adult; vertical lines, aged; dots, aged+β-gal; no fill, aged+Parvalbumin. *p<0.05 compared to adult; #p<0.05 compared to aged group+Ad.β-galGFP. Heart rates for each group are shown in Table 1.

 

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  		Table 1 The basal heart rates of different groups

 
3.3. Effect on force–frequency relationship
To test whether parvalbumin overexpression changes force–frequency relationship, we studied the effect of incremental atrial pacing on hemodynamic parameters in adult and aged F344 x BN rats. As shown in Fig. 4, +dP/dt increased with a rise in heart rate in adult hearts, but this rate-dependent response became negative in the aged hearts. In the aged hearts over-expressing parvalbumin, there was no decrease in the maximal rate of pressure rise, and the diastolic function is improved (Table 2). Similar results were observed in F344 rats (data not shown).


Figure 4
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  		Fig. 4 Effect of incremental atrial pacing on +dP/dt.Effect of incremental atrial pacing on +dP/dt in adult Fisher 344 x BN hearts(n=6; lhblk), aged hearts F344 x BN (n=6; bullet) and aged F344 x BN hearts infected with Ad.β-galGFP (n=6; {blacktriangleup}) or Ad.Parvalbumin (n=6; {blacktriangledown}). The baseline heart rates for each group are shown in Table 1 and the baseline systolic and diastolic pressures are shown in Figs. 2 and 3Go. *p<0.05 compared to aged group.

 

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  		Table 2 The diastolic parameters (–dP/dt, mmHg/s) during the force–frequency test

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
4.1. Hemodynamic changes in aging
Abnormal cardiac relaxation and diastolic dysfunction have been widely described in rat models of senescence [4,5]. However, it has been recently emphasized that the underlying pathology of the aging rat strain may affect cardiac function [11,23]. In order to broaden the impact of our findings, we studied two distinctly different rat strains:

(1) the Fischer 344 which is characterized by significant fibrosis within the myocardium and
(2) the Fischer 344 x Brown Norway F1 hybrid which exhibits minimal fibrosis [23].

Furthermore, different lifespans exist in those two rats strains. While F344 is at very old age and can be considered senescent at 26-month, the F344/BN rats live significantly longer than F344. They do not reach senescence until closer to 34 months [24]. In both rat strains, aging did not alter systolic parameters. However, both rat strains exhibited significant diastolic dysfunction, suggesting that this is a ubiquitous finding in aging and not limited to different rat strains.

4.2. Effects of parvalbumin overexpression
SR Ca2+-ATPase is the major pump regulating diastolic Ca2+ uptake and thereby relaxation in mammalian myocardium. It has been hypothesized that a decrease in SERCA is responsible for the observed diastolic dysfunction. We found a 40–50% decrease in SERCA in the aging myocardium in both the F344 and the F344 x BN strains. This is consistent with observations that a decrease in cardiac SERCA mRNA, protein expression and function is prevalent in animal models of senescence as well as in aging humans[8–10,13,25]. The observation that in vivo overexpression of SERCA normalized the diastolic dysfunction in aged F344 rats corroborated this hypothesis. Increasing the number of SERCA pumps may increase energy expenditure. At baseline SR Ca2+-ATPase activity is responsible for about 15% of myocardial energy consumption [26]. It has been reported that a decrease in energy reserve contributes to contractile dysfunction in heart failure [27]. Increasing the number of SR Ca2+-ATPase pumps by gene transfer may increase energy requirements in the heart and therefore not benefit the aging heart with diastolic failure. Because parvalbumin works via an ATP-independent mechanism, overexpression of parvalbumin may circumvent the energy consumption problem. Here we have shown that in vivo overexpression of parvalbumin improved the diastolic abnormalities observed in aging myocardium but have no effects on systolic parameters. This is in contrast to findings by Szatkowski et al. [20] who reported an increase in peak LV pressure in normal rats over-expressing parvalbumin. In single myocytes, overexpression of parvalbumin did not increase parameters of shortening [19]. Both authors have provided evidence that overexpression of parvalbumin may be beneficial in pathological states with diastolic dysfunction, i.e., hypothyroidism. Here we have provided evidence that the overexpression of parvalbumin may be beneficial in aging where diastolic dysfunction is prevalent [7]. At rest, the diastolic dysfunction found in the aging heart may be of little consequence. However, the cardiovascular response to pacing is decreased in the elderly and in experimental models of senescence [3,22]. We observed that overexpression of parvalbumin improved the negative force–frequency relationship in the aged hearts. Parvalbumin overexpression may therefore be especially beneficial at higher heart rates, i.e., under stress.

4.3. Cellular mechanism for improved diastolic function by gene transfer of parvalbumin
The cellular mechanism for improved diastolic function by gene transfer of parvalbumin was investigated in a separated in vitro study [28]. In that study, myocytes were isolated from 26- and 6-month F344/BN hybrid rats and were infected with Ad.Parvalbumin and Ad.β-gal, respectively. Introduction of parvalbumin into myocytes significantly increased the rate of calcium transient decay and the rate of myocytes re-lengthening in aging myocytes, thus, corrects impaired relaxation prevailing in aging myocytes. This in vitro study is correlated with and provided the cellular mechanism to interpret the improved diastolic function in our current in vivo study. Nevertheless, caution should be taken when we translate the in vitro observations into in vivo studies because the complexity of the multifactorial and multicellular work-loaded performance in the intact heart may not be fully reflected in studies from isolated myocytes.

In summary, we reported that overexpression of parvalbumin improves diastolic dysfunction in two different rat models of senescence; thus, this effect is independent of the rat strain investigated. The results show promises that gene therapy of parvalbumin may address the impaired Ca2+ homeostasis and diastolic dysfunction without increasing energy expenditure.


   Acknowledgements
 
This work is supported by a NIH/NHLBI 5 K08 HL-697782 grant and an Older Americans Independence Center (OAIC) Grant to Ulrich Schmidt.


   Notes
 
Time for primary review 21 days


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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