Hormonal regulation of β-myosin heavy chain expression in the mouse left ventricle

Patrizio, Mario; Musumeci, Marco; Piccone, Ambra; Raggi, Carla; Mattei, Elisabetta; Marano, Giuseppe

doi:10.1530/joe-12-0201

Cited by 12 publications

(8 citation statements)

References 44 publications

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“…An increase in the relative abundance of the ␤-isoform of MHC is a marker for pathological hypertrophy (11,24) and is associated with slower contractile and relaxation kinetics (19,28,38). The ability of TRV120023 to prevent the change in the relative abundance of MHC isoforms agrees with our findings that TRV120023 also prevents the hypertrophic response to ANG II.…”

Section: Discussionsupporting

confidence: 87%

The β-arrestin-biased ligand TRV120023 inhibits angiotensin II-induced cardiac hypertrophy while preserving enhanced myofilament response to calcium

Monasky

Taglieri

Henze

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Monasky MM, Taglieri DM, Henze M, Warren CM, Utter MS, Soergel DG, Violin JD, Solaro RJ. The ␤-arrestin-biased ligand TRV120023 inhibits angiotensin II-induced cardiac hypertrophy while preserving enhanced myofilament response to calcium. In the present study, we compared the cardioprotective effects of TRV120023, a novel angiotensin II (ANG II) type 1 receptor (AT1R) ligand, which blocks G protein coupling but stimulates ␤-arrestin signaling, against treatment with losartan, a conventional AT1R blocker in the treatment of cardiac hypertrophy and regulation of myofilament activity and phosphorylation. Rats were subjected to 3 wk of treatment with saline, ANG II, ANG II ϩ losartan, ANG II ϩ TRV120023, or TRV120023 alone. ANG II induced increased left ventricular mass compared with rats that received ANG II ϩ losartan or ANG II ϩ TRV120023. Compared with saline controls, ANG II induced a significant increase in pCa50 and maximum Ca 2ϩ -activated myofilament tension but reduced the Hill coefficient (nH). TRV120023 increased maximum tension and pCa50, although to lesser extent than ANG II. In contrast to ANG II, TRV120023 increased nH. Losartan blocked the effects of ANG II on pCa 50 and nH and reduced maximum tension below that of saline controls. ANG II ϩ TRV120023 showed responses similar to those of TRV120023 alone; compared with ANG II ϩ losartan, ANG II ϩ TRV120023 preserved maximum tension and increased both pCa 50 and cooperativity. Tropomyosin phosphorylation was lower in myofilaments from saline-treated hearts compared with the other groups. Phosphorylation of cardiac troponin I was significantly reduced in ANG II ϩ TRV120023 and TRV120023 groups versus saline controls, and myosin-binding protein C phosphorylation at Ser 282 was unaffected by ANG II or losartan but significantly reduced with TRV120023 treatment compared with all other groups. Our data indicate that TRV120023-related promotion of ␤-arrestin signaling and enhanced contractility involves a mechanism promoting the myofilament response to Ca 2ϩ via altered protein phosphorylation. Selective activation of ␤-arrestin-dependent pathways may provide advantages over conventional AT 1R blockers.␤-arrestin; hypertrophy; angiotensin; myofilament calcium sensitivity; angiotensin II type 1 receptor THERAPIES that act through the pharmacological inhibition of the renin-angiotensin-aldosterone system are routinely and effectively used, often as the first line of treatment of hypertension, chronic heart failure, cardiac remodeling after myocardial infarction, and diabetic nephropathy (6, 16). Three groups of pharmaceuticals, angiotensin-converting enzyme inhibitors, angiotensin II (ANG II) type 1 receptor (AT 1 R) blockers (ARBs), and mineralcorticoid antagonists, have been used for the past 35 yr to attenuate or reverse hypertension-induced myocardial hypertrophy and to reduce morbidity and mortality of cardiovascular disease (25, 37a, 37b).Activation of the AT 1 R, a G protein-coupled receptor, plays a pivotal role in the regulation of cardiovascular physi...

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Section: Discussionsupporting

confidence: 87%

The β-arrestin-biased ligand TRV120023 inhibits angiotensin II-induced cardiac hypertrophy while preserving enhanced myofilament response to calcium

Monasky

Taglieri

Henze

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…It is possible that normally occurring episodes of tachycardia that are associated with the menstrual cycle could cumulatively promote the stable expression of a greater amount of MHC-␤ and thereby account for the observed sex-related difference in the left atrium in the present study. The loss of estrogen with menopause could also account for the greater level of MHC-␤ in the female left atrium since ovariectomy in animals models, with or without estrogen replacement, clearly demonstrates a dependence of cardiac myosin isoform expression on hormone levels (30,37,54). The unusually high level of MHC-␤ in the left atrium of the 26-year-old nonfailing woman, with a possible abnormal sex hormone status (see RESULTS), is consistent with a dependency of cardiac MHC isoform expression on circulating estrogen.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in myosin heavy chain isoforms of human failing and nonfailing atria

Reiser

Moravec

2014

American Journal of Physiology-Heart and Circulatory Physiology

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Reiser PJ, Moravec CS. Sex differences in myosin heavy chain isoforms of human failing and nonfailing atria. Mammalian hearts express two myosin heavy chain (MHC) isoforms, which drive contractions with different kinetics and power-generating ability. The expression of the isoform that is associated with more rapid contraction kinetics and greater power output, MHC-␣, is downregulated, with a concurrent increase in the relative amount of the slower isoform, MHC-␤, during the progression to experimentally induced or disease-related heart failure. This change in protein expression has been well studied in right and left ventricles in heart failure models and in humans with failure. Relatively little quantitative data exists regarding MHC isoform expression shifts in human failing atria. We previously reported significant increases in the relative amount of MHC-␤ in the human failing left atrium. The results of that study suggested that there might be a sex-related difference in the level of MHC-␤ in the left atrium, but the number of female subjects was insufficient for statistical analysis. The objective of this study was to test whether there is, in fact, a sex-related difference in the level of MHC-␤ in the right and left atria of humans with cardiomyopathy. The results indicate that significant differences exist in atrial MHC isoform expression between men and women who are in failure. The results also revealed an unexpected twofold greater amount of MHC-␤ in the nonfailing left atrium of women, compared with men. The observed sex-related differences in MHC isoform expression could impact ventricular diastolic filling during normal daily activities, as well as during physiologically stressful events. heart; sex; myosin; heart failure

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“…28, 29, 50 In fact, several of these genes have been shown to be regulated by the presence of estrogen. 51, 52 Despite dramatic differences in heart rate and ATP use, MyHC isoform ratios change in response to pathological stimuli in a manner similar to humans, therefore making smaller animals appropriate for use as CVD models.…”

Section: Sexual Dimorphisms In Human and Rodent Cardiovascular Physiomentioning

confidence: 99%

The Importance of Biological Sex and Estrogen in Rodent Models of Cardiovascular Health and Disease

Blenck

Harvey

Reckelhoff

et al. 2016

Circulation Research

161

131

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Nearly one-third of deaths in the United States are caused by cardiovascular disease (CVD) each year. In the past, CVD was thought to mainly affect men leading to the exclusion of women and female animals from clinical studies and preclinical research. In light of sexual dimorphisms in CVD, a need exists to examine baseline cardiac differences in humans and the animals used to model CVD. In humans, sex differences are apparent at every level of cardiovascular physiology from action potential duration and mitochondrial energetics to cardiac myocyte and whole heart contractile function. Biological sex is an important modifier of the development of CVD with younger women generally being protected, but this cardioprotection is lost later in life, suggesting a role for estrogen. While endogenous estrogen is most likely a mediator of the observed functional differences in both health and disease, the signaling mechanisms involved are complex and are not yet fully understood. To investigate how sex modulates CVD development, animal models are essential tools and should be useful in the development of therapeutics. This review will focus on describing the cardiovascular sexual dimorphisms that exist both physiologically as well as in common animal models of CVD.

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Hormonal regulation of β-myosin heavy chain expression in the mouse left ventricle

Cited by 12 publications

References 44 publications

The β-arrestin-biased ligand TRV120023 inhibits angiotensin II-induced cardiac hypertrophy while preserving enhanced myofilament response to calcium

The β-arrestin-biased ligand TRV120023 inhibits angiotensin II-induced cardiac hypertrophy while preserving enhanced myofilament response to calcium

Sex differences in myosin heavy chain isoforms of human failing and nonfailing atria

The Importance of Biological Sex and Estrogen in Rodent Models of Cardiovascular Health and Disease

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