Physiology - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 7 of 7
  • Item
    Thumbnail Image
    Cardiomyocyte Functional Etiology in Heart Failure With Preserved Ejection Fraction Is Distinctive-A New Preclinical Model
    Curl, CL ; Danes, VR ; Bell, JR ; Raaijmakers, AJA ; Ip, WTK ; Chandramouli, C ; Harding, TW ; Porrello, ER ; Erickson, JR ; Charchar, FJ ; Kompa, AR ; Edgley, AJ ; Crossman, DJ ; Soeller, C ; Mellor, KM ; Kalman, JM ; Harrap, S ; Delbridge, LMD (WILEY, 2018-06-05)
    BACKGROUND: Among the growing numbers of patients with heart failure, up to one half have heart failure with preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF is a substantial and escalating unmet clinical need-and the lack of HFpEF-specific animal models represents a major preclinical barrier in advancing understanding of HFpEF. As established treatments for heart failure with reduced ejection fraction (HFrEF) have proven ineffective for HFpEF, the contention that the intrinsic cardiomyocyte phenotype is distinct in these 2 conditions requires consideration. Our goal was to validate and characterize a new rodent model of HFpEF, undertaking longitudinal investigations to delineate the associated cardiac and cardiomyocyte pathophysiology. METHODS AND RESULTS: The selectively inbred Hypertrophic Heart Rat (HHR) strain exhibits adult cardiac enlargement (without hypertension) and premature death (40% mortality at 50 weeks) compared to its control strain, the normal heart rat. Hypertrophy was characterized in vivo by maintained systolic parameters (ejection fraction at 85%-90% control) with marked diastolic dysfunction (increased E/E'). Surprisingly, HHR cardiomyocytes were hypercontractile, exhibiting high Ca2+ operational levels and markedly increased L-type Ca2+ channel current. In HHR, prominent regions of reparative fibrosis in the left ventricle free wall adjacent to the interventricular septum were observed. CONCLUSIONS: Thus, the cardiomyocyte remodeling process in the etiology of this HFpEF model contrasts dramatically with the suppressed Ca2+ cycling state that typifies heart failure with reduced ejection fraction. These findings may explain clinical observations, that treatments considered appropriate for heart failure with reduced ejection fraction are of little benefit for HFpEF-and suggest a basis for new therapeutic strategies.
  • Item
    Thumbnail Image
    Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney
    Jiang, X ; Eales, JM ; Scannali, D ; Nazgiewicz, A ; Prestes, P ; Maier, M ; Denniff, M ; Xu, X ; Saluja, S ; Cano-Gamez, E ; Wystrychowski, W ; Szulinska, M ; Antczak, A ; Byars, S ; Skrypnik, D ; Glyda, M ; Krol, R ; Zywiec, J ; Zukowska-Szczechowska, E ; Burrell, LM ; Woolf, AS ; Greenstein, A ; Bogdanski, P ; Keavney, B ; Morris, AP ; Heagerty, A ; Williams, B ; Harrap, SB ; Trynka, G ; Samani, NJ ; Guzik, TJ ; Charchar, FJ ; Tomaszewski, M (OXFORD UNIV PRESS, 2020-12-21)
    AIMS: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. METHODS AND RESULTS: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. CONCLUSION: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.
  • Item
    Thumbnail Image
    Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure
    Marques, FZ ; Prestes, PR ; Byars, SG ; Ritchie, SC ; Wurtz, P ; Patel, SK ; Booth, SA ; Rana, I ; Minoda, Y ; Berzins, SP ; Curl, CL ; Bell, JR ; Wai, B ; Srivastava, PM ; Kangas, AJ ; Soininen, P ; Ruohonen, S ; Kahonen, M ; Lehtimaki, T ; Raitoharju, E ; Havulinna, A ; Perola, M ; Raitakari, O ; Salomaa, V ; Ala-Korpela, M ; Kettunen, J ; McGlynn, M ; Kelly, J ; Wlodek, ME ; Lewandowski, PA ; Delbridge, LM ; Burrell, LM ; Inouye, M ; Harrap, SB ; Charchar, FJ (WILEY, 2017-06-01)
    BACKGROUND: Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. METHODS AND RESULTS: We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression. CONCLUSIONS: Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.
  • Item
    No Preview Available
    Nerve growth factor gene locus explains elevated renal nerve growth factor mRNA in young spontaneously hypertensive rats
    Charchar, FJ ; Kapuscinski, MK ; Harrap, SB (LIPPINCOTT WILLIAMS & WILKINS, 1998-10-01)
    Nerve growth factor (NGF) controls the growth of sympathetic nerves and is increased in young spontaneously hypertensive rats (SHR). The NGF gene has been linked genetically with hypertension in the SHR strain and may explain high NGF mRNA levels. To test for genetic linkage between the NGF gene and its expression in vivo, we examined renal NGF mRNA levels in male SHR, control Donryu rats (DRY), and F2 rats derived from SHR and DRY at ages 2, 4, 10, and 20 weeks. Tail-cuff blood pressure was measured at 4, 10, and 20 weeks of age. NGF mRNA levels in SHR (NGF genotype: SS) were higher than those in DRY (NGF genotype: DD) at 2, 4, and 10 weeks of age (P<0.0001) but the same at 20 weeks of age. In the F2 generation, the S allele was associated with significantly (P=0.01) higher renal NGF mRNA levels at 2 weeks of age. Mean NGF mRNA levels fell (P=0.01) with age in F2 rats, and the difference between SS and DD genotype F2 rats diminished at older ages and was not significant. In F2 rats there was a positive correlation between the number of NGF S alleles inherited and tail-cuff pressure (P<0.007). Our findings indicate that the NGF locus is an important regulator of NGF mRNA levels. It is likely that mutations in or near the NGF gene explain in part high early NGF gene expression in SHR.
  • Item
    No Preview Available
    Persistent reduction in renal nerve growth factor mRNA after perindopril treatment of young spontaneously hypertensive rats
    Charchar, FJ ; Kapuscinski, M ; Harrap, SB (LIPPINCOTT WILLIAMS & WILKINS, 1998-02-01)
    Nerve growth factor (NGF) determines sympathetic innervation of target tissues, and NGF levels are increased in young spontaneously hypertensive rats (SHR). Angiotensin can affect NGF levels, and the persistent reduction in blood pressure after brief angiotensin-converting enzyme inhibition in young SHR may involve long-term changes in NGF and sympathetic innervation. We measured the relative abundance of renal NGF mRNA by reverse transcription-polymerase chain reaction in SHR during and after treatment from 6 to 10 weeks of age with vehicle, perindopril (3 mg/kg per day), the bradykinin B2 antagonist Hoe 140 (0.5 mg/kg per day), both perindopril and Hoe 140, or angiotensin II (Ang II; 200 ng/kg per minute). Glomerular filtration rates were estimated at 10 and 20 weeks of age. At 10 weeks of age, Ang II caused a significant (P<.01) increase and perindopril caused a significant (P<.01) decrease in renal NGF mRNA levels. Blockade of the bradykinin B2 receptor during perindopril treatment attenuated (P<.05) the reduction in NGF mRNA levels. Renal NGF mRNA (P=.005) and blood pressure (P<.001) remained significantly lower than control 10 weeks after perindopril treatment was stopped. The partial reduction in blood pressure at 20 weeks of age in rats that had received perindopril and Hoe 140 was not associated with any difference in renal NGF mRNA. Perindopril-induced long-term reduction in renal NGF mRNA levels may decrease sympathetic innervation and thereby contribute to the long-term posttreatment blood pressure reduction.
  • Item
    No Preview Available
    Nerve growth factor gene and hypertension in spontaneously hypertensive rats
    Kapuscinski, M ; Charchar, F ; Innes, B ; Mitchell, GA ; Norman, TL ; Harrap, SB (LIPPINCOTT WILLIAMS & WILKINS, 1996-02-01)
    OBJECTIVE: High blood pressure in spontaneously hypertensive rat (SHR) is associated with increased sympathetic innervation of key tissues, possibly as the result of increased nerve growth factor (NGF). The aim of this study was to test for genetic linkage of the NGF gene to high blood pressure. DESIGN: We studied NGF gene expression in young SHR and examined linkage of the NGF locus to mean arterial pressure in genetically segregating crosses of SHR and normotensive Donryu (DRY) rats. METHODS: NGF mRNA was measured by Northern blot, and a restriction fragment length polymorphism of the NGF gene revealed after digestion with the NsiI restriction enzyme was used to study inheritance. RESULTS: Levels of NGF mRNA were detected easily in the kidneys of 2-, 4- and 10-week-old SHR but not in age-matched DRY rats. In an F2 population, the blood pressure of rats homozygous for the DRY NGF allele was 6 mmHg less than in heterozygotes and 8 mmHg less than in rats homozygous for the SHR NGF allele (analysis of variance, P < 0.004). In backcross rats the blood pressure of NGF heterozygotes was not significantly different from that of SHR homozygotes. CONCLUSION: These results indicate differences in renal NGF mRNA in SHR during the development of hypertension and suggest that a genetic locus in or near the NGF gene contributes in a Mendelian dominant pattern to a significant increment in blood pressure in SHR.
  • Item
    Thumbnail Image
    Council for High Blood Pressure Research/InterAmerican Society of Hypertension/International Society of Hypertension: First New Investigators Symposium at the High Blood Pressure Research 2011 Scientific Sessions
    Veerabhadrappa, P ; Burger, D ; Charchar, F ; Tomaszewski, M ; Carlberg, B ; Harrap, S ; Touyz, RM (LIPPINCOTT WILLIAMS & WILKINS, 2012-02-01)