Mitochondrial biogenesis during pressure overload induced cardiac hypertrophy in adult rats

Existing literature provides an equivocal picture of the behavior of mitochondrial synthesis during the time course of cardiac hypertrophy. Therefore, we examined the effect of cardiac hypertrophy on mitochondrial cytochrome c oxidase (CYTOX) activity, the content of CYTOX subunit VIc mRNA, and the expression of molecular chaperones. Adult male Sprague–Dawley rats were subjected to either abdominal aortic constriction to induce pressure overload (PO) or a sham operation (SH). Animals were studied 2, 4, 7, 14, 21, or 28 days after surgery. Aortic constriction resulted in a significant elevation in arterial pressure by 4 days after surgery. Significant (p < 0.05) hypertrophy was attained by 4 days and was stabilized at 37% between 7 and 28 days. CYTOX activity (U/g) did not differ significantly between PO and SH animals at either early (<7 days) or later time points, indicating that mitochondrial content increased in proportion to adaptive cellular hypertrophic growth. The concentration of the molecular chaperones HSP60 and GRP75 involved in mitochondrial protein import did not change with PO treatment. The levels of mRNAs encoding both CYTOX subunit VIc and HSP60 remained constant, in proportion to cardiac growth. This suggests that the accelerated synthesis of CYTOX and HSP60 during cardiac hypertrophy is regulated transcriptionally. The data help to resolve the controversy in the literature regarding mitochondrial biogenesis during moderate, stable cardiac hypertrophy, and they indirectly indicate that proportional mitochondrial synthesis relative to cellular hypertrophy is regulated at the transcriptional level.Key words: hypertension, cytochrome c oxidase, mRNA, cytochrome c oxidase subunits, aortic constriction, heat shock proteins, molecular chaperones.

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Piezo1-Mediated Mechanotransduction Promotes Cardiac Hypertrophy by Impairing Calcium Homeostasis to Activate Calpain/Calcineurin Signaling

Hypertension ◽

10.1161/hypertensionaha.121.17177 ◽

2021 ◽

Author(s):

Yuhao Zhang ◽

Sheng-an Su ◽

Wudi Li ◽

Yuankun Ma ◽

Jian Shen ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Ion Channel ◽

Calcium Homeostasis ◽

Pressure Overload ◽

Cell Physiology ◽

Hypertrophic Growth ◽

Molecular Features ◽

Mechanosensitive Ion Channel

Hemodynamic overload induces pathological cardiac hypertrophy, which is an independent risk factor for intractable heart failure in long run. Beyond neurohumoral regulation, mechanotransduction has been recently recognized as a major regulator of cardiac hypertrophy under a myriad of conditions. However, the identification and molecular features of mechanotransducer on cardiomyocytes are largely sparse. For the first time, we identified Piezo1 (Piezo type mechanosensitive ion channel component 1), a novel mechanosensitive ion channel with preference to Ca 2+ was remarkably upregulated under pressure overload and enriched near T-tubule and intercalated disc of cardiomyocyte. By applying cardiac conditional Piezo1 knockout mice (Piezo1 fl/fl Myh6Cre+, Piezo1 Cko ) undergoing transverse aortic constriction, we demonstrated that Piezo1 was required for the development of cardiac hypertrophy and subsequent adverse remodeling. Activation of Piezo1 by external mechanical stretch or agonist Yoda1 lead to the enlargement of cardiomyocytes in vitro, which was blocked by Piezo1 silencing or Yoda1 analog Dooku1 or Piezo1 inhibitor GsMTx4. Mechanistically, Piezo1 perturbed calcium homeostasis, mediating extracellular Ca 2+ influx and intracellular Ca 2+ overload, thereby increased the activation of Ca 2+ -dependent signaling, calcineurin, and calpain. Inhibition of calcineurin or calpain could abolished Yoda1 induced upregulation of hypertrophy markers and the hypertrophic growth of cardiomyocytes in vitro. From a comprehensive view of the cardiac transcriptome, most of Piezo1 affected genes were highly enriched in muscle cell physiology, tight junction, and corresponding signaling. This study characterizes an undefined role of Piezo1 in pressure overload induced cardiac hypertrophy. It may partially decipher the differential role of calcium under pathophysiological condition, implying a promising therapeutic target for cardiac dysfunction.

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Leonurine Attenuates Pressure-Overload Cardiac Hypertrophy Induced By Abdominal Aortic Constriction In Rats

10.21203/rs.3.rs-516132/v1 ◽

2021 ◽

Author(s):

Ding Xiaoli ◽

Yuan Qingqing ◽

Qian Haibing

Keyword(s):

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Pressure Overload ◽

Ventricular Myocardium ◽

Left Ventricular ◽

Left Ventricular Myocardium ◽

Ang Ii ◽

Aortic Constriction ◽

Qrt Pcr ◽

Abdominal Aortic

Abstract Background: Myocardial hypertrophy occurs in many cardiovascular diseases. Leonurine (Leo) is commonly used for cardiovascular and cerebrovascular diseases. However, whether it can prevent cardiac hypertrophy is not known. The aim of this study was to investigate the effect and mechanism of Leonurine (Leo) against pressure-overload cardiac hypertrophy induced by abdominal aortic constriction (AAC) in rats. Methods: To answer this question, we prove it in the following way: Cardiac function was evaluated by hemodynamic; the left ventricle enlargement was measured by heart weight index (HWI) and left ventricular mass index (LVWI); myocardial tissue changes and myocardial cell diameter (MD) were determined by Hematoxylin and eosin (HE) staining; theβ-myosin heavy chain(β-MHC)and atrial natriuretic factor (ANF), which are recognized as a marker of cardiac hypertrophy, were determined by Real-time quantitative PCR (qRT-PCR), then another gene phospholipase C (PLC), inositol triphosphate (IP3), which associated with RAS were determined by Western blot(WB). angiotensin II (Ang II), angiotensin II type 1 receptor (AT1R) were determined by ELISA, WB and qRT-PCR methods. Finally, we measured the level of Ca2+ by microplate method and the protooncogene c-fos and c-myc mRNA in left ventricular myocardium by qRT-PCR.Results: Compare with control group, Leonurine can improve systolic dysfunction; inhibit the increase of left cardiac; inhibit myocardial cells were abnormally large and restrain the changes of cardiac histopathology; decrease the expression of β-MHC, ANF, Ang II, AT1R, c-fos and c-myc mRNA and the protein levels of PLC, IP3, AngII and AT1R in left ventricular myocardium, in addition, the content of Ca2+ also decrease. Conclusion: Therefore, Leonurine can inhibit cardiac hypertrophy induced by AAC and its effects may be associated with RAS.

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Rpm2, the Protein Subunit of Mitochondrial RNase P in Saccharomyces cerevisiae, Also Has a Role in the Translation of Mitochondrially Encoded Subunits of Cytochrome c Oxidase

Genetics ◽

10.1093/genetics/158.2.573 ◽

2001 ◽

Vol 158 (2) ◽

pp. 573-585

Author(s):

Vilius Stribinskis ◽

Guo-Jian Gao ◽

Steven R Ellis ◽

Nancy C Martin

Keyword(s):

Saccharomyces Cerevisiae ◽

Cytochrome C ◽

Cytochrome C Oxidase ◽

Mitochondrial Biogenesis ◽

Mitochondrial Protein ◽

Nuclear Gene ◽

Rnase P ◽

Wild Type ◽

Protein Subunit ◽

Mitochondrial Translation

Abstract RPM2 is a Saccharomyces cerevisiae nuclear gene that encodes the protein subunit of mitochondrial RNase P and has an unknown function essential for fermentative growth. Cells lacking mitochondrial RNase P cannot respire and accumulate lesions in their mitochondrial DNA. The effects of a new RPM2 allele, rpm2-100, reveal a novel function of RPM2 in mitochondrial biogenesis. Cells with rpm2-100 as their only source of Rpm2p have correctly processed mitochondrial tRNAs but are still respiratory deficient. Mitochondrial mRNA and rRNA levels are reduced in rpm2-100 cells compared to wild type. The general reduction in mRNA is not reflected in a similar reduction in mitochondrial protein synthesis. Incorporation of labeled precursors into mitochondrially encoded Atp6, Atp8, Atp9, and Cytb protein was enhanced in the mutant relative to wild type, while incorporation into Cox1p, Cox2p, Cox3p, and Var1p was reduced. Pulse-chase analysis of mitochondrial translation revealed decreased rates of translation of COX1, COX2, and COX3 mRNAs. This decrease leads to low steady-state levels of Cox1p, Cox2p, and Cox3p, loss of visible spectra of aa3 cytochromes, and low cytochrome c oxidase activity in mutant mitochondria. Thus, RPM2 has a previously unrecognized role in mitochondrial biogenesis, in addition to its role as a subunit of mitochondrial RNase P. Moreover, there is a synthetic lethal interaction between the disruption of this novel respiratory function and the loss of wild-type mtDNA. This synthetic interaction explains why a complete deletion of RPM2 is lethal.

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Apocynum Tablet Protects against Cardiac Hypertrophy via Inhibiting AKT and ERK1/2 Phosphorylation after Pressure Overload

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2014/769515 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9

Author(s):

Jianyong Qi ◽

Qin Liu ◽

Kaizheng Gong ◽

Juan Yu ◽

Lei Wang ◽

...

Keyword(s):

Chinese Medicine ◽

Cardiac Hypertrophy ◽

Protein Expression ◽

Molecular Mechanisms ◽

Cardiac Fibrosis ◽

Pressure Overload ◽

Study Groups ◽

Transverse Aortic Constriction ◽

Aortic Constriction ◽

Cardioprotective Effects

Background. Cardiac hypertrophy occurs in many cardiovascular diseases. Apocynum tablet (AT), a traditional Chinese medicine, has been widely used in China to treat patients with hypertension. However, the underlying molecular mechanisms of AT on the hypertension-induced cardiac hypertrophy remain elusive. The current study evaluated the effect and mechanisms of AT on cardiac hypertrophy.Methods. We created a mouse model of cardiac hypertrophy by inducing pressure overload with surgery of transverse aortic constriction (TAC) and then explored the effect of AT on the development of cardiac hypertrophy using 46 mice in 4 study groups (combinations of AT and TAC). In addition, we evaluated the signaling pathway of phosphorylation of ERK1/2, AKT, and protein expression of GATA4 in the cardioprotective effects of AT using Western blot.Results. AT inhibited the phosphorylation of Thr202/Tyr204 sites of ERK1/2, Ser473 site of AKT, and protein expression of GATA4 and significantly inhibited cardiac hypertrophy and cardiac fibrosis at 2 weeks after TAC surgery (P<0.05).Conclusions. We experimentally demonstrated that AT inhibits cardiac hypertrophy via suppressing phosphorylation of ERK1/2 and AKT.

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Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1721298115 ◽

2018 ◽

Vol 115 (30) ◽

pp. E7129-E7138 ◽

Cited By ~ 31

Author(s):

Shinichiro Sunamura ◽

Kimio Satoh ◽

Ryo Kurosawa ◽

Tomohiro Ohtsuki ◽

Nobuhiro Kikuchi ◽

...

Keyword(s):

Oxidative Stress ◽

Pulmonary Hypertension ◽

Cardiac Hypertrophy ◽

Cardiac Dysfunction ◽

High Throughput Screening ◽

Histological Analysis ◽

Rho Kinase ◽

Pressure Overload ◽

Aortic Constriction ◽

Patients With Heart Failure

Although postcapillary pulmonary hypertension (PH) is an important prognostic factor for patients with heart failure (HF), its pathogenesis remains to be fully elucidated. To elucidate the different roles of Rho-kinase isoforms, ROCK1 and ROCK2, in cardiomyocytes in response to chronic pressure overload, we performed transverse aortic constriction (TAC) in cardiac-specific ROCK1-deficient (cROCK1−/−) and ROCK2-deficient (cROCK2−/−) mice. Cardiomyocyte-specific ROCK1 deficiency promoted pressure-overload-induced cardiac dysfunction and postcapillary PH, whereas cardiomyocyte-specific ROCK2 deficiency showed opposite results. Histological analysis showed that pressure-overload-induced cardiac hypertrophy and fibrosis were enhanced in cROCK1−/− mice compared with controls, whereas cardiac hypertrophy was attenuated in cROCK2−/− mice after TAC. Consistently, the levels of oxidative stress were up-regulated in cROCK1−/− hearts and down-regulated in cROCK2−/− hearts compared with controls after TAC. Furthermore, cyclophilin A (CyPA) and basigin (Bsg), both of which augment oxidative stress, enhanced cardiac dysfunction and postcapillary PH in cROCK1−/− mice, whereas their expressions were significantly lower in cROCK2−/− mice. In clinical studies, plasma levels of CyPA were significantly increased in HF patients and were higher in patients with postcapillary PH compared with those without it. Finally, high-throughput screening demonstrated that celastrol, an antioxidant and antiinflammatory agent, reduced the expressions of CyPA and Bsg in the heart and the lung, ameliorating cardiac dysfunction and postcapillary PH induced by TAC. Thus, by differentially affecting CyPA and Bsg expressions, ROCK1 protects and ROCK2 jeopardizes the heart from pressure-overload HF with postcapillary PH, for which celastrol may be a promising agent.

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Altered renal dopamine receptors during development of cardiac hypertrophy

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1992.262.5.e569 ◽

1992 ◽

Vol 262 (5) ◽

pp. E569-E573

Author(s):

P. K. Ganguly ◽

K. Mukherjee ◽

Y. Chen

Keyword(s):

Cardiac Hypertrophy ◽

Dopamine Receptors ◽

Pressure Overload ◽

Total Body Weight ◽

Left Ventricular ◽

Kidney Cortex ◽

Sprague Dawley ◽

Aortic Constriction ◽

Compensatory Response ◽

Abdominal Aortic

The characteristics of dopamine receptors were studied in heart and kidney using the radiolabeled receptor assay of [3H]spiperone during the development of cardiac hypertrophy. Male Sprague-Dawley rats (175-200 g) underwent abdominal aortic constriction above the renal arteries and were studied 3, 14, and 28 days thereafter. Sham-operated animals without aortic constriction were used as control. Although the ratio of left ventricular weight to total body weight was significantly increased 14 and 28 days after aortic constriction in animals, [3H]spiperone binding in left ventricular membrane was increased as early as 3 days after aortic constriction. At 14 days, the binding was still elevated and, by 28 days, it returned to control values. In contrast, membranes obtained from kidney cortex showed an elevation of [3H]spiperone binding only at 28 days after aortic constriction; at 3 days the binding values were decreased. A reciprocal correlation was found between the number of dopamine receptors and the activity of Na(+)-K(+)-ATPase at 28 days of aortic constriction; the enzyme activity, as measured by the release of 32Pi from [gamma-32P]ATP, was decreased in kidney cortex. Autoradiographic data also showed an increased number of dopamine receptors in kidney at 28 days after abdominal aortic constriction. These results suggest that the dopamine receptor is increased very early in heart in response to pressure overload as a result of a compensatory response to maintain an optimal left ventricular output. Kidney dopamine receptors are triggered at a later stage possibly to maintain fluid homeostasis secondary to the cardiac hypertrophic process.

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Ascending Aortic Constriction in Rats for Creation of Pressure Overload Cardiac Hypertrophy Model

Journal of Visualized Experiments ◽

10.3791/50983 ◽

2014 ◽

Cited By ~ 3

Author(s):

Ajith Kumar GS ◽

Binil Raj ◽

Santhosh Kumar S ◽

Sanjay G ◽

Chandrasekharan Cheranellore Kartha

Keyword(s):

Cardiac Hypertrophy ◽

Pressure Overload ◽

Aortic Constriction

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Mitochondrial DNA replication and transcription are dissociated during embryonic cardiac hypertrophy

AJP Cell Physiology ◽

10.1152/ajpcell.1991.261.6.c1091 ◽

1991 ◽

Vol 261 (6) ◽

pp. C1091-C1098 ◽

Cited By ~ 7

Author(s):

J. M. Kennedy ◽

S. R. Lobacz ◽

S. W. Kelley

Keyword(s):

Mitochondrial Dna ◽

Cytochrome C ◽

Cardiac Hypertrophy ◽

Cytochrome C Oxidase ◽

Oxidase Activity ◽

Citrate Synthase ◽

Incubation Temperature ◽

Mitochondrial Gene ◽

Gene Replication ◽

Mitochondrial Dna Copy Number

Cardiac hypertrophy was produced in embryonic chicks by decreasing the incubation temperature from 38 degrees C to 32 degrees C on day 11. Increases in ventricular protein, RNA, and DNA support the cardiac enlargement. Cytochrome-c oxidase activity and citrate synthase activity were depressed in hypothermic ventricles by 63% and 56%, respectively. No significant differences were seen in enzyme activities in pectoralis muscles. The involvement of mitochondrial gene replication and transcription was evaluated using a cDNA clone for the mitochondrially encoded subunit III of cytochrome-c oxidase (CO III). Quantitative slot-blot analysis demonstrated that the relative CO III mRNA concentration was reduced in hypothermic ventricles. In contrast, the relative mitochondrial DNA concentration was increased in hypothermic ventricles. Taken together, these data indicate that a hypothermia-induced decrease in cytochrome-c oxidase activity is associated with a decrease in CO III mRNA, which is not coupled to a decrease in the mitochondrial DNA copy number. This dissociation of mitochondrial gene replication and transcription may provide a useful model for examining the regulation of mitochondrial biogenesis.

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