Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation - PubMed (original) (raw)

Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation

Annarosa Leri et al. EMBO J. 2003.

Abstract

Cardiac failure is a frequent cause of death in the aging human population. Telomere attrition occurs with age, and is proposed to be causal for the aging process. To determine whether telomere shortening leads to a cardiac phenotype, we studied heart function in the telomerase knockout mouse, Terc-/-. We studied Terc-/- mice at the second, G2, and fifth, G5, generation. Telomere shortening in G2 and G5 Terc-/- mice was coupled with attenuation in cardiac myocyte proliferation, increased apoptosis and cardiac myocyte hypertrophy. On a single-cell basis, telomere shortening was coincidental with increased expression of p53, indicating the presence of dysfunctional telomeres in cardiac myocytes from G5 Terc-/- mice. The impairment in cell division, the enhanced cardiac myocyte death and cellular hypertrophy, are concomitant with ventricular dilation, thinning of the wall and cardiac dysfunction. Thus, inhibition of cardiac myocyte replication provoked by telomere shortening, results in de-compensated eccentric hypertrophy and heart failure in mice. Telomere shortening with age could also contribute to cardiac failure in humans, opening the possibility for new therapies.

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Figures

Fig. 1. Telomere length analysis of WT and Terc–/– cardiac myocytes. (A) Representative confocal microscopy image showing FITC–PNA telomeric fluorescence on isolated nuclei (see Materials and methods). Cardiomyocyte nuclei were obtained from a G5 Terc–/– mouse (top panel). Lymphoma cells with short telomeres (L5178Y-S cells, 7 kbp; middle panel) and lymphoma cells with long telomeres (L5178Y cells, 48 kbp; bottom panel) are shown for comparison (McIlrath et al., 2001). Nuclei are illustrated by the blue fluorescence of propidium iodide (PI), and the red fluorescent dots correspond to telomeres. Bar = 10 µm. (B and C) Telomere fluorescence frequency histograms of WT, G2 and G5 Terc–/– cardiomyocytes derived from either young (2–4 months old, B) or older (6–8 months old, C) mice after Q-FISH with a Cy3-labeled telomere-specific probe (Materials and methods). Telomere length is shown as a.u.f. Three mice of each genotype were used for the analysis. The total numbers of nuclei and telomere dots used for the analysis are also indicated. Average telomere fluorescence values for each genotype expressed as a.u.f. are also shown together with the corresponding standard deviation. Note a higher frequency of nuclei with shorter telomeres in the G2 Terc–/– cardiac myocytes compared with the corresponding wild-types. This frequency is increased further in G5 Terc–/– cardiac myocytes. Statistical significance calculations are also shown. (D) Comparison of relative telomere fluorescence in young (2–4 months old) and aged (6–8 months old) G5 Terc–/– cardiac myocytes (ratio G5 Terc–/– interphase fluorescence/wild-type average fluorescence). A higher number of cardiac myocytes show low telomere fluorescence ratio values in the aged G5 Terc–/– mice compared with the younger animals. The difference is statistically significant (P < 0.0001).

Fig. 1. Telomere length analysis of WT and Terc–/– cardiac myocytes. (A) Representative confocal microscopy image showing FITC–PNA telomeric fluorescence on isolated nuclei (see Materials and methods). Cardiomyocyte nuclei were obtained from a G5 Terc–/– mouse (top panel). Lymphoma cells with short telomeres (L5178Y-S cells, 7 kbp; middle panel) and lymphoma cells with long telomeres (L5178Y cells, 48 kbp; bottom panel) are shown for comparison (McIlrath et al., 2001). Nuclei are illustrated by the blue fluorescence of propidium iodide (PI), and the red fluorescent dots correspond to telomeres. Bar = 10 µm. (B and C) Telomere fluorescence frequency histograms of WT, G2 and G5 Terc–/– cardiomyocytes derived from either young (2–4 months old, B) or older (6–8 months old, C) mice after Q-FISH with a Cy3-labeled telomere-specific probe (Materials and methods). Telomere length is shown as a.u.f. Three mice of each genotype were used for the analysis. The total numbers of nuclei and telomere dots used for the analysis are also indicated. Average telomere fluorescence values for each genotype expressed as a.u.f. are also shown together with the corresponding standard deviation. Note a higher frequency of nuclei with shorter telomeres in the G2 Terc–/– cardiac myocytes compared with the corresponding wild-types. This frequency is increased further in G5 Terc–/– cardiac myocytes. Statistical significance calculations are also shown. (D) Comparison of relative telomere fluorescence in young (2–4 months old) and aged (6–8 months old) G5 Terc–/– cardiac myocytes (ratio G5 Terc–/– interphase fluorescence/wild-type average fluorescence). A higher number of cardiac myocytes show low telomere fluorescence ratio values in the aged G5 Terc–/– mice compared with the younger animals. The difference is statistically significant (P < 0.0001).

Fig. 1. Telomere length analysis of WT and Terc–/– cardiac myocytes. (A) Representative confocal microscopy image showing FITC–PNA telomeric fluorescence on isolated nuclei (see Materials and methods). Cardiomyocyte nuclei were obtained from a G5 Terc–/– mouse (top panel). Lymphoma cells with short telomeres (L5178Y-S cells, 7 kbp; middle panel) and lymphoma cells with long telomeres (L5178Y cells, 48 kbp; bottom panel) are shown for comparison (McIlrath et al., 2001). Nuclei are illustrated by the blue fluorescence of propidium iodide (PI), and the red fluorescent dots correspond to telomeres. Bar = 10 µm. (B and C) Telomere fluorescence frequency histograms of WT, G2 and G5 Terc–/– cardiomyocytes derived from either young (2–4 months old, B) or older (6–8 months old, C) mice after Q-FISH with a Cy3-labeled telomere-specific probe (Materials and methods). Telomere length is shown as a.u.f. Three mice of each genotype were used for the analysis. The total numbers of nuclei and telomere dots used for the analysis are also indicated. Average telomere fluorescence values for each genotype expressed as a.u.f. are also shown together with the corresponding standard deviation. Note a higher frequency of nuclei with shorter telomeres in the G2 Terc–/– cardiac myocytes compared with the corresponding wild-types. This frequency is increased further in G5 Terc–/– cardiac myocytes. Statistical significance calculations are also shown. (D) Comparison of relative telomere fluorescence in young (2–4 months old) and aged (6–8 months old) G5 Terc–/– cardiac myocytes (ratio G5 Terc–/– interphase fluorescence/wild-type average fluorescence). A higher number of cardiac myocytes show low telomere fluorescence ratio values in the aged G5 Terc–/– mice compared with the younger animals. The difference is statistically significant (P < 0.0001).

Fig. 1. Telomere length analysis of WT and Terc–/– cardiac myocytes. (A) Representative confocal microscopy image showing FITC–PNA telomeric fluorescence on isolated nuclei (see Materials and methods). Cardiomyocyte nuclei were obtained from a G5 Terc–/– mouse (top panel). Lymphoma cells with short telomeres (L5178Y-S cells, 7 kbp; middle panel) and lymphoma cells with long telomeres (L5178Y cells, 48 kbp; bottom panel) are shown for comparison (McIlrath et al., 2001). Nuclei are illustrated by the blue fluorescence of propidium iodide (PI), and the red fluorescent dots correspond to telomeres. Bar = 10 µm. (B and C) Telomere fluorescence frequency histograms of WT, G2 and G5 Terc–/– cardiomyocytes derived from either young (2–4 months old, B) or older (6–8 months old, C) mice after Q-FISH with a Cy3-labeled telomere-specific probe (Materials and methods). Telomere length is shown as a.u.f. Three mice of each genotype were used for the analysis. The total numbers of nuclei and telomere dots used for the analysis are also indicated. Average telomere fluorescence values for each genotype expressed as a.u.f. are also shown together with the corresponding standard deviation. Note a higher frequency of nuclei with shorter telomeres in the G2 Terc–/– cardiac myocytes compared with the corresponding wild-types. This frequency is increased further in G5 Terc–/– cardiac myocytes. Statistical significance calculations are also shown. (D) Comparison of relative telomere fluorescence in young (2–4 months old) and aged (6–8 months old) G5 Terc–/– cardiac myocytes (ratio G5 Terc–/– interphase fluorescence/wild-type average fluorescence). A higher number of cardiac myocytes show low telomere fluorescence ratio values in the aged G5 Terc–/– mice compared with the younger animals. The difference is statistically significant (P < 0.0001).

Fig. 2. Telomere length and p53 expression in myocyte nuclei. Myocyte nuclei are stained by a PNA probe (red fluorescence) and p53 (green fluorescence). Blue fluorescence corresponds to PI labeling. (A and B) Myocyte nuclei from the left ventricle of wild-type mice. (C and D) Myocyte nuclei from the left ventricle of G5 Terc–/– mice. Arrowheads point to nuclei with short telomeres and which are positive for p53. Bar = 10 µm. (E) The frequency distribution of telomere length in wild-type, G2 Terc–/– and G5 Terc–/– mice (open bars). The corresponding values for each subclass of nuclei expressing p53 are shown by solid bars. (F and G) p53 labeling of nuclei (bright fluorescence) in sections of the left ventricle of a wild-type (F) and G5 Terc–/– (G) mouse. Blue fluorescence corresponds to PI labeling and red fluorescence depicts α-sarcomeric actin antibody staining of the myocyte cytoplasm. Arrowheads point to p53 labeling of myocyte nuclei. Bar = 10 µm. (H) Percentages of myocyte nuclei labeled by p53 in wild-type (WT), G2 Terc–/– (G2) and G5 Terc–/– (G5) mice. Results are means ± SD. * and † indicate a difference, P < 0.005, versus WT and G2, respectively.

Fig. 2. Telomere length and p53 expression in myocyte nuclei. Myocyte nuclei are stained by a PNA probe (red fluorescence) and p53 (green fluorescence). Blue fluorescence corresponds to PI labeling. (A and B) Myocyte nuclei from the left ventricle of wild-type mice. (C and D) Myocyte nuclei from the left ventricle of G5 Terc–/– mice. Arrowheads point to nuclei with short telomeres and which are positive for p53. Bar = 10 µm. (E) The frequency distribution of telomere length in wild-type, G2 Terc–/– and G5 Terc–/– mice (open bars). The corresponding values for each subclass of nuclei expressing p53 are shown by solid bars. (F and G) p53 labeling of nuclei (bright fluorescence) in sections of the left ventricle of a wild-type (F) and G5 Terc–/– (G) mouse. Blue fluorescence corresponds to PI labeling and red fluorescence depicts α-sarcomeric actin antibody staining of the myocyte cytoplasm. Arrowheads point to p53 labeling of myocyte nuclei. Bar = 10 µm. (H) Percentages of myocyte nuclei labeled by p53 in wild-type (WT), G2 Terc–/– (G2) and G5 Terc–/– (G5) mice. Results are means ± SD. * and † indicate a difference, P < 0.005, versus WT and G2, respectively.

Fig. 2. Telomere length and p53 expression in myocyte nuclei. Myocyte nuclei are stained by a PNA probe (red fluorescence) and p53 (green fluorescence). Blue fluorescence corresponds to PI labeling. (A and B) Myocyte nuclei from the left ventricle of wild-type mice. (C and D) Myocyte nuclei from the left ventricle of G5 Terc–/– mice. Arrowheads point to nuclei with short telomeres and which are positive for p53. Bar = 10 µm. (E) The frequency distribution of telomere length in wild-type, G2 Terc–/– and G5 Terc–/– mice (open bars). The corresponding values for each subclass of nuclei expressing p53 are shown by solid bars. (F and G) p53 labeling of nuclei (bright fluorescence) in sections of the left ventricle of a wild-type (F) and G5 Terc–/– (G) mouse. Blue fluorescence corresponds to PI labeling and red fluorescence depicts α-sarcomeric actin antibody staining of the myocyte cytoplasm. Arrowheads point to p53 labeling of myocyte nuclei. Bar = 10 µm. (H) Percentages of myocyte nuclei labeled by p53 in wild-type (WT), G2 Terc–/– (G2) and G5 Terc–/– (G5) mice. Results are means ± SD. * and † indicate a difference, P < 0.005, versus WT and G2, respectively.

Fig. 2. Telomere length and p53 expression in myocyte nuclei. Myocyte nuclei are stained by a PNA probe (red fluorescence) and p53 (green fluorescence). Blue fluorescence corresponds to PI labeling. (A and B) Myocyte nuclei from the left ventricle of wild-type mice. (C and D) Myocyte nuclei from the left ventricle of G5 Terc–/– mice. Arrowheads point to nuclei with short telomeres and which are positive for p53. Bar = 10 µm. (E) The frequency distribution of telomere length in wild-type, G2 Terc–/– and G5 Terc–/– mice (open bars). The corresponding values for each subclass of nuclei expressing p53 are shown by solid bars. (F and G) p53 labeling of nuclei (bright fluorescence) in sections of the left ventricle of a wild-type (F) and G5 Terc–/– (G) mouse. Blue fluorescence corresponds to PI labeling and red fluorescence depicts α-sarcomeric actin antibody staining of the myocyte cytoplasm. Arrowheads point to p53 labeling of myocyte nuclei. Bar = 10 µm. (H) Percentages of myocyte nuclei labeled by p53 in wild-type (WT), G2 Terc–/– (G2) and G5 Terc–/– (G5) mice. Results are means ± SD. * and † indicate a difference, P < 0.005, versus WT and G2, respectively.

Fig. 3. Ventricular function and anatomy. (A–D) LV hemodynamics in WT (n = 10), G2 (n = 18) and G5 (n = 8) mice at sacrifice. (E–H) LV anatomy in WT (n = 8), G2 (n = 12) and G5 (n = 8) mice. Results are means ± SD. * and †, P < 0.05 versus WT and G2, respectively.

Fig. 3. Ventricular function and anatomy. (A–D) LV hemodynamics in WT (n = 10), G2 (n = 18) and G5 (n = 8) mice at sacrifice. (E–H) LV anatomy in WT (n = 8), G2 (n = 12) and G5 (n = 8) mice. Results are means ± SD. * and †, P < 0.05 versus WT and G2, respectively.

Fig. 4. Cardiomyocyte volume and number. (A–C) Average volume of each LV myocyte class. (D) Total number of LV myocytes. WT (n = 10), G2 (n = 10) and G5 (n = 8) mice. Results are means ± SD. * and †, P < 0.05 versus WT and G2, respectively.

Fig. 4. Cardiomyocyte volume and number. (A–C) Average volume of each LV myocyte class. (D) Total number of LV myocytes. WT (n = 10), G2 (n = 10) and G5 (n = 8) mice. Results are means ± SD. * and †, P < 0.05 versus WT and G2, respectively.

Fig. 5. Cardiomyocyte proliferation and death. BrdU (A–C) and Ki67 (D–F) labeling of LV myocytes from G2 mice. Nuclei are stained by PI (blue; A and D), and by BrdU (green; B) and Ki67 (green; E). Cardiomyocyte cytoplasm is stained by α-sarcomeric actin antibody (red; C and F). Bright fluorescence reflects the combination of PI and BrdU (C) or PI and Ki67 (F) labeling of nuclei. Bar = 10 µm. (G and H) Effects of the lack of telomerase on cardiomyocyte proliferation. WT (n = 8), G2 (n = 10 for BrdU and n = 9 for Ki67) and G5 (n = 9) mice. Results are means ± SD. * and †, P < 0.05 versus WT and G2, respectively. (I–K) Cardiomyocyte apoptosis in a G5 mouse. Nuclei are stained by PI (blue; I), and by hairpin 1 (green; J). Cardiac myocyte cytoplasm is stained by α-sarcomeric actin antibody (red; K). Bright fluorescence reflects the combination of PI and hairpin 1 (K) labeling of a myocyte nucleus. Bar = 10 µm. (L) Effects of the lack of telomerase on myocyte apoptosis. WT (n = 6), G2 (n = 9) and G5 (n = 9) mice. Results are means ± SD. *, P < 0.05 versus WT.

Fig. 5. Cardiomyocyte proliferation and death. BrdU (A–C) and Ki67 (D–F) labeling of LV myocytes from G2 mice. Nuclei are stained by PI (blue; A and D), and by BrdU (green; B) and Ki67 (green; E). Cardiomyocyte cytoplasm is stained by α-sarcomeric actin antibody (red; C and F). Bright fluorescence reflects the combination of PI and BrdU (C) or PI and Ki67 (F) labeling of nuclei. Bar = 10 µm. (G and H) Effects of the lack of telomerase on cardiomyocyte proliferation. WT (n = 8), G2 (n = 10 for BrdU and n = 9 for Ki67) and G5 (n = 9) mice. Results are means ± SD. * and †, P < 0.05 versus WT and G2, respectively. (I–K) Cardiomyocyte apoptosis in a G5 mouse. Nuclei are stained by PI (blue; I), and by hairpin 1 (green; J). Cardiac myocyte cytoplasm is stained by α-sarcomeric actin antibody (red; K). Bright fluorescence reflects the combination of PI and hairpin 1 (K) labeling of a myocyte nucleus. Bar = 10 µm. (L) Effects of the lack of telomerase on myocyte apoptosis. WT (n = 6), G2 (n = 9) and G5 (n = 9) mice. Results are means ± SD. *, P < 0.05 versus WT.

Fig. 5. Cardiomyocyte proliferation and death. BrdU (A–C) and Ki67 (D–F) labeling of LV myocytes from G2 mice. Nuclei are stained by PI (blue; A and D), and by BrdU (green; B) and Ki67 (green; E). Cardiomyocyte cytoplasm is stained by α-sarcomeric actin antibody (red; C and F). Bright fluorescence reflects the combination of PI and BrdU (C) or PI and Ki67 (F) labeling of nuclei. Bar = 10 µm. (G and H) Effects of the lack of telomerase on cardiomyocyte proliferation. WT (n = 8), G2 (n = 10 for BrdU and n = 9 for Ki67) and G5 (n = 9) mice. Results are means ± SD. * and †, P < 0.05 versus WT and G2, respectively. (I–K) Cardiomyocyte apoptosis in a G5 mouse. Nuclei are stained by PI (blue; I), and by hairpin 1 (green; J). Cardiac myocyte cytoplasm is stained by α-sarcomeric actin antibody (red; K). Bright fluorescence reflects the combination of PI and hairpin 1 (K) labeling of a myocyte nucleus. Bar = 10 µm. (L) Effects of the lack of telomerase on myocyte apoptosis. WT (n = 6), G2 (n = 9) and G5 (n = 9) mice. Results are means ± SD. *, P < 0.05 versus WT.

Fig. 5. Cardiomyocyte proliferation and death. BrdU (A–C) and Ki67 (D–F) labeling of LV myocytes from G2 mice. Nuclei are stained by PI (blue; A and D), and by BrdU (green; B) and Ki67 (green; E). Cardiomyocyte cytoplasm is stained by α-sarcomeric actin antibody (red; C and F). Bright fluorescence reflects the combination of PI and BrdU (C) or PI and Ki67 (F) labeling of nuclei. Bar = 10 µm. (G and H) Effects of the lack of telomerase on cardiomyocyte proliferation. WT (n = 8), G2 (n = 10 for BrdU and n = 9 for Ki67) and G5 (n = 9) mice. Results are means ± SD. * and †, P < 0.05 versus WT and G2, respectively. (I–K) Cardiomyocyte apoptosis in a G5 mouse. Nuclei are stained by PI (blue; I), and by hairpin 1 (green; J). Cardiac myocyte cytoplasm is stained by α-sarcomeric actin antibody (red; K). Bright fluorescence reflects the combination of PI and hairpin 1 (K) labeling of a myocyte nucleus. Bar = 10 µm. (L) Effects of the lack of telomerase on myocyte apoptosis. WT (n = 6), G2 (n = 9) and G5 (n = 9) mice. Results are means ± SD. *, P < 0.05 versus WT.

Fig. 5. Cardiomyocyte proliferation and death. BrdU (A–C) and Ki67 (D–F) labeling of LV myocytes from G2 mice. Nuclei are stained by PI (blue; A and D), and by BrdU (green; B) and Ki67 (green; E). Cardiomyocyte cytoplasm is stained by α-sarcomeric actin antibody (red; C and F). Bright fluorescence reflects the combination of PI and BrdU (C) or PI and Ki67 (F) labeling of nuclei. Bar = 10 µm. (G and H) Effects of the lack of telomerase on cardiomyocyte proliferation. WT (n = 8), G2 (n = 10 for BrdU and n = 9 for Ki67) and G5 (n = 9) mice. Results are means ± SD. * and †, P < 0.05 versus WT and G2, respectively. (I–K) Cardiomyocyte apoptosis in a G5 mouse. Nuclei are stained by PI (blue; I), and by hairpin 1 (green; J). Cardiac myocyte cytoplasm is stained by α-sarcomeric actin antibody (red; K). Bright fluorescence reflects the combination of PI and hairpin 1 (K) labeling of a myocyte nucleus. Bar = 10 µm. (L) Effects of the lack of telomerase on myocyte apoptosis. WT (n = 6), G2 (n = 9) and G5 (n = 9) mice. Results are means ± SD. *, P < 0.05 versus WT.

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