Biventricular Remodeling in Murine Models of Right Ventricular Pressure Overload

Kapur, Navin K.; Paruchuri, Vikram; Aronovitz, Mark; Qiao, Xiaoying; Mackey, Emily; Daly, Gerard H.; Ughreja, Kishan; Levine, Jonathan; Blanton, Robert M.; Hill, Nicholas S.; Karas, Richard H.

doi:10.1371/journal.pone.0070802

Cited by 21 publications

(33 citation statements)

References 25 publications

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“…Animal protocols were approved by the Tufts Medical Center Institutional Animal Care and Use Committee. As described previously, adult, male, 12–14 week old C57BL/6 wild-type (Eng+/+) and Eng+/− mice underwent constriction of the thoracic aorta (TAC) or pulmonary artery (PAC) for 8 weeks to generate models of left HF or right HF, respectively (Kapur et al, 2013; Kapur et al, 2012). Sham-operated mice served as controls (n=6).…”

Section: Methodsmentioning

confidence: 99%

Endoglin selectively modulates transient receptor potential channel expression in left and right heart failure

Morine

Paruchuri

Qiao

et al. 2016

Cardiovascular Pathology

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Introduction Transient receptor potential (TRP) channels are broadly expressed cation channels that mediate diverse physiological stimuli and include canonical (TRPC), melastatin (TRPM) and vanilloid (TRPV) subtypes. Recent studies have implicated a role for TRPC6 channels as an important component of signaling via the cytokine, transforming growth factor beta 1 (TGFb1) in right (RV) or left ventricular (LV) failure. Endoglin is a transmembrane glycoprotein that promotes TRPC6 expression and TGFb1 activity. No studies have defined biventricular expression of all TRP channel family members in heart failure. Hypothesis We hypothesized that heart failure is associated with distinct patterns of TRP channel expression in the LV and RV. Methods Paired viable left (LV) and right (RV) ventricular free wall tissue was obtained from human subjects with end-stage heart failure (n=12) referred for cardiac transplantation or biventricular assist device implantation. Paired LV and RV samples from human subjects without heart failure served as controls (n=3). To explore a functional role for endoglin (Eng) as a regulator of TRP expression in response to RV or LV pressure overload, wild-type (Eng+/+) and Eng haploinsufficient (Eng+/−) mice were exposed to thoracic aortic (TAC) or pulmonary arterial (PAC) constriction for 8 weeks. Biventricular tissue was analyzed by real-time polymerase chain reaction. Results Compared to non-failing human LV and RV samples, mRNA levels of TRPC1, 3, 4, 6 and TRPV-2 were increased and TRPM2, 3, and 8 were decreased in failing LV and RV samples. TRPC1 and 6 levels were higher in failing RV compared to failing LV samples. After TAC, murine LV levels of TPRC1 and 6 were increased in both Eng +/+ and Eng +/− mice compared to sham controls. LV levels of TRPC4; TRPM3 and 7; TRPV2 and 4 were increased in Eng +/+, not Eng +/− mice after TAC. After PAC, all TRP channel family members were increased in the RV, but not LV, of Eng +/+ compared to sham controls. In contrast to Eng+/+, PAC did not increase RV or LV levels of TRP channels in Eng +/− mice. Conclusions This is the first study to demonstrate that TRP channels exhibit distinct profiles of expression in the LV and RV of patients with heart failure and in murine models of univentricular pressure overload. We further introduce that the TGFb1 co-receptor endoglin selectively regulates expression of multiple TRP channels in the setting of LV or RV pressure overload.

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Section: Methodsmentioning

confidence: 99%

Endoglin selectively modulates transient receptor potential channel expression in left and right heart failure

Morine

Paruchuri

Qiao

et al. 2016

Cardiovascular Pathology

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“…PCR was performed in triplicate using 40 cycles at 94°C for 15 seconds, 60°C for 30 seconds and 72°C for 30 seconds with an ABI Prism 7900 Sequence Detection System. Primers for 18S ribosomal RNA, Endoglin, TGF-β1, β-MHC, SERCA, Type I collagen and plasminogen activator inhibitor I (PAI-I) were used as described previously [6–8]. Primer sequences for activin like kinase-1 (ALK-1) were 5′-TGA CTT TCT GCA GAG GCA GA and 3′-CGA CTC AAA GCA GTC TGT GC, for activin like kinase 5 (ALK-5) were 5- ATC CAT CAC TAG ATC GCC CT and 3′-CGA TGG ATC AGA AGG TAC AAG A, for BMP-7 were 5′-ACC CTT CAT GGT GGC CTT CT and 3′-CCT CAG GGC CTC TTG GTT CT, for BMP-9 were 5′-TGT ACA ACA GGT ACA CGT CCG and 3′-TGA ATG TCC TGG GAC ACC AG, for brain natriuretic peptide (BNP) were 5′-GTG AGG CCT TGG TCC TTC AA and 3′-CAC CGC TGG GAG GTC ACT and for connective tissue growth factor (CTGF) were 5′-AGC CTC AAA CTC CAA ACA CC and 3′-CAA CAG GGA TTT GAC CAC.…”

Section: Methodsmentioning

confidence: 99%

Conditional knockout of activin like kinase-1 (ALK-1) leads to heart failure without maladaptive remodeling

et al. 2017

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Activin like kinase-1 (ALK-1) mediates signaling via the transforming growth factor beta (TGFβ) family of ligands. ALK-1 activity promotes endothelial proliferation and migration. Reduced ALK-1 activity is associated with arteriovenous malformations. No studies have examined the effect of global ALK-1 deletion on indices of cardiac remodeling. We hypothesized that reduced levels of ALK-1 promote maladaptive cardiac remodeling. Methods We studied ALK-1 conditional knockout mice (cKO) harboring the ROSA26-CreER knock-in allele whereby a single dose of intraperitoneal tamoxifen triggered ubiquitous Cre-recombinase mediated excision of floxed ALK-1 alleles. Tamoxifen treated wild-type (WT-TAM; n=5) and vehicle treated ALK-1-cKO mice (cKO-CON; n=5) served as controls for tamoxifen treated ALK-1-cKO mice (cKO-TAM; n=15). Results ALK-1 cKO-TAM mice demonstrated reduced 14-day survival compared to cKO-CON controls (13% vs 100%, respectively, p<0.01). Seven days after treatment, cKO-TAM mice began to exhibit reduced left ventricular (LV) fractional shortening, progressive LV dilation, and gastrointestinal bleeding. After 14 days total body mass was reduced, but LV and lung mass increased in cKO-TAM not cKO-CON mice. Peak LV systolic pressure, contractility, and arterial elastance were reduced, but LV end-diastolic pressure and stroke volume were increased in cKO-TAM, not cKO-CON mice. LV ALK-1 mRNA levels were reduced in cKO-TAM, not cKO-CON mice. LV levels of other TGFβ-family ligands and receptors (ALK5, TBRII, BMPRII, Endoglin, BMP7, BMP9, and TGFβ1) were unchanged between groups. Cardiomyocyte area and LV levels of BNP were increased in cKO-TAM mice, but LV levels of β-MHC and SERCA were unchanged. No increase in markers of cardiac fibrosis, Type I collagen, CTGF, or PAI-1, were observed between groups. No differences were observed for any variable studied between cKO-CON and WT-TAM mice. Conclusion Global deletion of ALK-1 is associated with the development of high output heart failure without maladaptive remodeling. Future studies exploring the functional role of ALK-1 in cardiac remodeling independent of systemic AVMs are required.

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“…Animal protocols were approved by the Tufts Medical Center Institutional Animal Care and Use Committee. Adult, male, 12–14 week old wild-type ( Alk1 +/+ ) and Alk1 +/− mice underwent transverse aortic constriction (TAC) for 2 weeks using a 27G needle to generate left ventricular (LV) pressure overload [4, 12]. Sham-operated mice served as controls (n=6/group).…”

Section: Methodsmentioning

confidence: 99%

“…Sham-operated mice served as controls (n=6/group). At the conclusion of the studies, terminal hemodynamics were recorded using biventricular conductance catheters as previously described [12]. LV tissue was rinsed with sterile saline and stored for subsequent biochemical and histological analysis.…”

Section: Methodsmentioning

confidence: 99%

“…PCR was performed in triplicate using 40 cycles at 94 ° C for 15 seconds, 60 ° C for 30 seconds and 72 ° C for 30 seconds with an ABI Prism 7900 Sequence Detection System. Primers for 18S ribosomal RNA, Endoglin, TGF-β1, beta-myosin heavy chain (β-MHC), sarcoplasmic endoplasmic reticulum ATPase (SERCA), Type I collagen, and calcineurin were described previously [4, 12]. Primer sequences for Alk1 were 5′-TGA CTT TCT GCA GAG GCA GA and 3′- CGA CTC AAA GCA GTC TGT GC, and for connective tissue growth factor (CTGF) were 5′- AGC CTC AAA CTC CAA ACA CC and 3′- CAA CAG GGA TTT GAC CAC.…”

Section: Methodsmentioning

confidence: 99%

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Reduced activin receptor-like kinase 1 activity promotes cardiac fibrosis in heart failure

Morine

Qiao

Paruchuri

et al. 2017

Cardiovascular Pathology

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Introduction Activin receptor-like kinase 1 (ALK1) mediates signaling via the transforming growth factor beta-1 (TGFβ1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. Hypothesis We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure. Methods and Results In patients with advanced heart failure referred for left ventricular (LV) assist device implantation, LV Alk1 mRNA and protein levels were lower than control LV obtained from patients without heart failure. To investigate the role of ALK1 in heart failure, Alk1 haploinsufficient (Alk1+/−) and wild-type (WT) mice were studied 2 weeks after severe transverse aortic constriction (TAC). LV and lung weights were higher in Alk1+/− mice after TAC. Cardiomyocyte area and LV mRNA levels of brain natriuretic peptide and β-myosin heavy chain were increased similarly in Alk1+/− and WT mice after TAC. Alk-1 mice exhibited reduced Smad 1 phosphorylation and signaling compared to WT mice after TAC. Compared to WT, LV fibrosis and Type 1 Collagen mRNA and protein levels were higher in Alk1+/− mice. LV fractional shortening was lower in Alk1+/− mice after TAC Conclusions Reduced expression of ALK1 promotes cardiac fibrosis and impaired LV function in a murine model of heart failure. Further studies examining the role of ALK1 and ALK1 inhibitors on cardiac remodeling are required.

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Biventricular Remodeling in Murine Models of Right Ventricular Pressure Overload

Cited by 21 publications

References 25 publications

Endoglin selectively modulates transient receptor potential channel expression in left and right heart failure

Endoglin selectively modulates transient receptor potential channel expression in left and right heart failure

Conditional knockout of activin like kinase-1 (ALK-1) leads to heart failure without maladaptive remodeling

Reduced activin receptor-like kinase 1 activity promotes cardiac fibrosis in heart failure

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