Time course of decompensation after angiotensin II and high-salt diet in Balb/CJ mice suggests pulmonary hypertension-induced cardiorenal syndrome

Becirovic‐Agic, Mediha; Jönsson, Sofia; Tveitarås, Maria K.; Skogstrand, Trude; Karlsen, Tine Veronika; Lidén, Åsa; Leh, Sabine; Ericsson, Madelene; Nilsson, Stefan K.; Reed, Rolf K.; Hultström, Michael

doi:10.1152/ajpregu.00373.2018

Cited by 4 publications

(5 citation statements)

References 32 publications

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“…Interestingly, this is also described in Balb/CJ mice, where AngII treatment in combination with a high-salt diet did not induce hypertension, but induced cardiac decompensation. This was attributed to the development of acute pulmonary hypertension (Becirovic-Agic et al, 2019). Lastly, heart problems in Atg7 F/F SM22α-Cre + mice can develop due to temporal expression of the SM22 gene in cardiomyocytes during embryonic development (Lepore et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Defective Autophagy in Vascular Smooth Muscle Cells Alters Vascular Reactivity of the Mouse Femoral Artery

et al. 2020

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Autophagy is an important cellular survival process that enables degradation and recycling of defective organelles and proteins to maintain cellular homeostasis. Hence, defective autophagy plays a role in many age-associated diseases, such as atherosclerosis, arterial stiffening and hypertension. Recently, we showed in mice that autophagy in vascular smooth muscle cells (VSMCs) of large elastic arteries such as the aorta is important for Ca 2+ mobilization and vascular reactivity. Whether autophagy plays a role in the smaller muscular arteries, such as the femoral artery, and thereby contributes to for example, blood pressure regulation is currently unknown. Therefore, we determined vascular reactivity of femoral artery segments of mice containing a VSMC specific deletion of the essential autophagy gene Atg7 (Atg7 F/F SM22α-Cre +) and compared them to femoral artery segments of corresponding control mice (Atg7 +/+ SM22α-Cre +). Our results indicate that similar to the aorta, femoral artery segments showed enhanced contractility. Specifically, femoral artery segments of Atg7 F/F SM22α-Cre + mice showed an increase in phasic phenylephrine (PE) induced contractions, together with an enhanced sensitivity to depolarization induced contractions. In addition, and importantly, VSMC sensitivity to exogenous nitric oxide (NO) was significantly increased in femoral artery segments of Atg7 F/F SM22α-Cre + mice. Notwithstanding the fact that small artery contractility is a significant pathophysiological determinant for the development of hypertension, 7 days of treatment with angiotensin II (AngII), which increased systolic blood pressure in control mice, was ineffective in Atg7 F/F SM22α-Cre + mice. It is likely that this was due to the increased sensitivity of VSMCs to NO in the femoral artery, although changes in the heart upon AngII treatment were also present, which could also be (partially) accountable for the lack of an AngII-induced rise in blood pressure in Atg7 F/F SM22α-Cre + mice. Overall, our study indicates that apart from previously shown effects on large elastic arteries, VSMC autophagy also plays a pivotal role in the regulation of the contractile and relaxing properties of the smaller muscular arteries. This may suggest a role for autophagy in vascular pathologies, such as hypertension and arterial stiffness.

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Section: Discussionmentioning

confidence: 99%

Defective Autophagy in Vascular Smooth Muscle Cells Alters Vascular Reactivity of the Mouse Femoral Artery

et al. 2020

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“…Balb/CJ develop cardiac hypertrophy with early restriction of pulmonary flow, abnormal left ventricle filling, and reduced cardiac output, which leads to lower urine excretion and edema development. C57BL/6J on the other hand develop hypertension and cardiac hypertrophy without any signs of impaired cardiac function (3). The main finding of this study is that the response to ANG IIϩSalt is genetically linked.…”

Section: Discussionmentioning

confidence: 61%

“…QTL on chromosome 3 is associated with change in cardiac output. We have previously seen that ANG IIϩSalt increases cardiac output in C57BL/6J and slightly reduces cardiac output in Balb/CJ mice (3). In F2 mice, ANG IIϩSalt reduced cardiac output in some mice and increased cardiac output in others.…”

Section: Resultsmentioning

confidence: 91%

“…Despite the high prevalence and mortality, an optimal treatment strategy for the syndrome has not been defined, and there is still a large gap in our understanding of the molecular pathophysiol-ogy (1,8). In previous studies, we have seen that a combination of angiotensin II and high-salt diet (ANG IIϩSalt) induces cardiac hypertrophy both in Balb/CJ and C57BL/6J mice, but only Balb/CJ mice exhibit an impaired cardiac performance (3). In addition, ANG IIϩSalt induces early restriction of pulmonary flow and abnormal left ventricular filling in Balb/CJ mice, which is associated with fluid retention, edema, and substantial mortality.…”

Section: Introductionmentioning

confidence: 99%

“…Despite decreased urine excretion Balb/CJ mice have lower cardiac output than C57BL/6J mice and signs of diastolic dysfunction. C57BL/6J mice on the other hand develop hypertension and cardiac hypertrophy while on ANG IIϩSalt treatment, but without signs of impaired cardiac performance and, importantly, without early decompensation and death (3,12).…”

Section: Introductionmentioning

confidence: 99%

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Quantitative trait loci associated with angiotensin II and high-salt diet induced acute decompensated heart failure in Balb/CJ mice

Becirovic‐Agic

Jönsson

Hultström

2019

Physiological Genomics

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Genetic background of different mouse strains determines their susceptibility to disease. We have previously shown that Balb/CJ and C57BL/6J mice develop cardiac hypertrophy to the same degree when treated with a combination of angiotensin II and high-salt diet (ANG II+Salt), but only Balb/CJ show impaired cardiac function associated with edema development and substantial mortality. We hypothesized that the different response to ANG II+Salt is due to the different genetic backgrounds of Balb/CJ and C57BL/6J. To address this we performed quantitative trait locus (QTL) mapping of second filial generation (F2) of mice derived from a backcross between Balb/CJ and first filial generation (F1) of mice. Cardiac function was measured with echocardiography, glomerular filtration rate using FITC-inulin clearance, fluid and electrolyte balance in metabolic cages, and blood pressure with tail-cuff at baseline and on the fourth day of treatment with ANG II+Salt. A total of nine QTLs were found to be linked to different phenotypes in ANG II+Salt-treated F2 mice. A QTL on chromosome 3 was linked to cardiac output, and a QTL on chromosome 12 was linked to isovolumic relaxation time. QTLs on chromosome 2 and 3 were linked to urine excretion and sodium excretion. Eight genes located at the different QTLs contained coding nonsynonymous SNPs published in the mouse genome database that differ between Balb/CJ and C57BL/6J. In conclusion, ANG II+Salt-induced acute decompensation in Balb/CJ is genetically linked to several QTLs, indicating a multifaceted phenotype. The present study identified potential candidate genes that may represent important pathways in acute decompensated heart failure.

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Angiotensin II and salt-induced decompensation in Balb/CJ mice is aggravated by fluid retention related to low oxidative stress

Jönsson

Becirovic‐Agic

Isackson

et al. 2019

American Journal of Physiology-Renal Physiology

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Balb/CJ mice are more sensitive to treatment with angiotensin II (ANG II) and high-salt diet compared with C57BL/6J mice. Together with higher mortality, they develop edema, signs of heart failure, and acute kidney injury. The aim of the present study was to identify differences in renal gene regulation that may affect kidney function and fluid balance, which could contribute to decompensation in Balb/CJ mice after ANG II + salt treatment. Male Balb/CJ and C57BL/6J mice were divided into the following five different treatment groups: control, ANG II, salt, ANG II + salt, and ANG II + salt + N-acetylcysteine. Gene expression microarrays were used to explore differential gene expression after treatment and between the strains. Published data from the Mouse Genome Database were used to identify the associated genomic differences. The glomerular filtration rate (GFR) was measured using inulin clearance, and fluid balance was measured using metabolic cages. Gene ontology enrichment analysis of gene expression microarrays identified glutathione transferase (antioxidant system) as highly enriched among differentially expressed genes. Balb/CJ mice had similar GFR compared with C57BL/6J mice but excreted less Na+ and water, although net fluid and electrolyte balance did not differ, suggesting that Balb/CJ mice may be inherently more prone to decompensation. Interestingly, C57BL/6J mice had higher urinary oxidative stress despite their relative protection from decompensation. In addition, treatment with the antioxidant N-acetylcysteine decreased oxidative stress in C57BL/6J mice, reduced urine excretion, and increased mortality. Balb/CJ mice are more sensitive than C57BL/6J to ANG II + salt, in part mediated by lower oxidative stress, which favors fluid and Na+ retention.

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Time course of decompensation after angiotensin II and high-salt diet in Balb/CJ mice suggests pulmonary hypertension-induced cardiorenal syndrome

Cited by 4 publications

References 32 publications

Defective Autophagy in Vascular Smooth Muscle Cells Alters Vascular Reactivity of the Mouse Femoral Artery

Defective Autophagy in Vascular Smooth Muscle Cells Alters Vascular Reactivity of the Mouse Femoral Artery

Quantitative trait loci associated with angiotensin II and high-salt diet induced acute decompensated heart failure in Balb/CJ mice

Angiotensin II and salt-induced decompensation in Balb/CJ mice is aggravated by fluid retention related to low oxidative stress

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