Pharmacological Inhibition of ε-Protein Kinase C Attenuates Cardiac Fibrosis and Dysfunction in Hypertension-Induced Heart Failure

Inagaki, Kenji; Koyanagi, Tomoyoshi; Berry, Natalia; Sun, Lihan; Mochly‐Rosen, Daria

doi:10.1161/hypertensionaha.107.109637

Cited by 52 publications

(63 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although olmesartan did not attenuate salt-induced hypertension ( Figure 7A), it did suppress LV hypertrophy, maintain LV systolic function, and improve survival over the duration of the study, as reported previously (data not shown). 26 Notably, olmesartan blocked the salt-induced increase in adrenal aldosterone biosynthesis ( Figure 7B …”

Section: Effects Of a High-salt Diet On The Adrenal Rasmentioning

confidence: 94%

Biphasic Time Course of the Changes in Aldosterone Biosynthesis Under High-Salt Conditions in Dahl Salt-Sensitive Rats

Morizane

Mitani

Ozawa

et al. 2012

ATVB

View full text Add to dashboard Cite

Objective-The comorbidity of excess salt and elevated plasma aldosterone has deleterious effects in cardiovascular disease. We evaluated the mechanisms behind the paradoxical increase in aldosterone biosynthesis in relation to dietary intake of salt. Methods and Results-Dahl salt-sensitive (Dahl-S) and salt-resistant (Dahl-R) rats were fed a high-salt diet, and plasma and tissue levels of aldosterone in the adrenal gland and heart were quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry. In Dahl-S rats, we found that the delayed and paradoxical increase in aldosterone biosynthesis after the initial and appropriate response to high salt. The late rise in aldosterone biosynthesis was accompanied by upregulation of CYP11B2 expression in the zona glomerulosa and increased adrenal angiotensin II levels and renin-angiotensin system components. It preceded the appearance of left ventricular systolic dysfunction and renal insufficiency. Blockade of angiotensin AT 1 receptors reversed the paradoxical increase in aldosterone biosynthesis. In contrast, Dahl-R rats maintained the initial suppression of aldosterone biosynthesis. Aldosterone levels in the heart closely paralleled those in the plasma and adrenal gland and disappeared after bilateral adrenalectomy. Conclusion-Chronic salt overload in Dahl-S rats stimulates aberrant aldosterone production via activation of the local renin-angiotensin system in the adrenal gland, thereby creating the comorbidity of excess salt and elevated plasma aldosterone. (Arterioscler Thromb Vasc Biol . 2012;32:1194-1203 .)

show abstract

Section: Effects Of a High-salt Diet On The Adrenal Rasmentioning

confidence: 94%

Biphasic Time Course of the Changes in Aldosterone Biosynthesis Under High-Salt Conditions in Dahl Salt-Sensitive Rats

Morizane

Mitani

Ozawa

et al. 2012

ATVB

View full text Add to dashboard Cite

show abstract

“…Its sub-depressor dose is relatively variable to be determined, because earlier studies using a Dahl saltsensitive rat model have reported that 0.6 or 3 mg kg À1 day À1 of olmesartan did not lower blood pressure but that 2.5 mg kg À1 day À1 of the drug did. [15][16][17] Therefore, we have carefully carried out our preliminary study in our system and determined that 0.6 and 1 mg kg À1 day À1 of olmesartan were sub-depressor doses. Systolic blood pressure and heart rate were measured every 2 weeks with a tail-cuff system (MK-2000, Muromachi, Tokyo, Japan).…”

Section: Animal Preparationmentioning

confidence: 99%

Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin–angiotensin system in hypertensive rats

et al. 2009

View full text Add to dashboard Cite

Diabetes mellitus (DM) is a major risk factor for heart failure, independent of coronary artery disease or hypertension (HT). Therefore, our study was designed to examine the mechanisms of DM-induced left ventricular (LV) diastolic dysfunction. In this study, we made five different 10-week treatment groups of Dahl salt-sensitive rats as follows: Control; a low-salt (0.5% NaCl) diet, HT; a high-salt (5% NaCl) diet, DM; a low-salt diet with streptozotocin (STZ) injection (30 mg kg À1 i.p.), HT+DM; a highsalt diet with STZ injection, and the Olmesartan group; a high-salt diet with STZ treated with an angiotensin receptor blocker, olmesartan (1 mg kg À1 day À1 ). Cardiac diastolic dysfunction with a preserved systolic function was noted in the HT group, and was most prominently noted in the HT+DM group, characterized by enhanced cardiac fibrosis, whereas the extent of HT and myocardial hypertrophy was comparable between the two groups. Myocardial expressions of collagen III, transforming growth factor-b2, angiotensin-converting enzyme (ACE), angiotensin II type-1 receptor and myocardial oxidative stress (evaluated by 4-hydroxy-2-nonenal-modified protein) were mostly enhanced in the HT+DM group. Importantly, there was a positive correlation between the extent of diastolic dysfunction and that of myocardial ACE expression. All these cardiac abnormalities induced by DM and HT were ameliorated in the olmesartan group. These results indicate that DM accelerates diastolic dysfunction in hypertensive heart disease through activation of the renin-angiotensin system, with subsequent inflammatory and oxidative stresses and myocardial fibrosis, suggesting that an inhibition of the system is effective for the treatment of diastolic dysfunction in this combined disorder.

show abstract

“…Previous studies reported that Cav3 contributes to a variety of cardiac pathophysiological processes such as arrhythmogenesis, myocardial hypertrophy, and myocardial ischemia/reperfusion injury [17-19]. Cav3 was shown to be associated with protein kinase C (PKC) signaling, known to induce fibrogenesis [20-22]. PKC belongs to a family of Ser/Thr protein kinases, commonly expressed in eukaryotic cells, and several subtypes have been identified, including PKCα, PKCβ, PKCδ, and PKCε [23].…”

Section: Introductionmentioning

confidence: 99%

Abnormal Downregulation of Caveolin-3 Mediates the Pro-Fibrotic Action of MicroRNA-22 in a Model of Myocardial Infarction

Zhang¹,

Yin²,

Jiao³

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Cardiac fibrosis is an important cardiac remodeling event that can ultimately lead to the development of severe arrhythmia and heart failure. MicroRNAs (miRNAs) are involved in the pathogenesis of many cardiovascular diseases. Here, we aimed to investigate the effects of caveolin-3 (Cav3) on the pathogenesis of cardiac fibrosis and the underlying molecular mechanisms. Methods: Cav3 expression was decreased in cardiac fibrosis in vivo and in vitro model. To investigate the role of Cav3 in cardiac fibrosis, we transfected cardiac fibroblasts (CFs) with the siRNA of Cav3 and Cav3-overexpressing plasmid. The collagen content and proliferation of CFs were detected by qRT-PCR, western blot, MTT, and immunofluorescence. A luciferase reporter gene assay and gain/loss of function were used to detect the relationship between miR-22 and Cav3. Results: Cav3 depletion in CFs induced an increase in collagen content, cell proliferation, and phenotypic conversion of fibroblasts to myofibroblasts. Conversely, Cav3 overexpression in CFs was shown to inhibit angiotensin II-mediated excessive collagen deposition through protein kinase C (PKC)ε inactivation. Cav3 was experimentally confirmed as a direct target of miR-22, containing two seed binding sites in its 3′-untranslated region, and miR-22 was demonstrated to be significantly upregulated in the ischemic border zone in mice after myocardial infarction and in neonatal rat CFs pretreated with angiotensin II. miR-22 overexpression increased CFs proliferation, and collagen and α-smooth muscle actin levels in CFs, while the knockdown of endogenous miR-22 decreased CFs numbers. Conclusions: Our findings demonstrate that miR-22 accelerates cardiac fibrosis through the miR-22-Cav3-PKCε pathway, which, therefore, may represent a new therapeutic target for treatment of excessive fibrosis-associated cardiac diseases.

show abstract

Pharmacological Inhibition of ε-Protein Kinase C Attenuates Cardiac Fibrosis and Dysfunction in Hypertension-Induced Heart Failure

Cited by 52 publications

References 15 publications

Biphasic Time Course of the Changes in Aldosterone Biosynthesis Under High-Salt Conditions in Dahl Salt-Sensitive Rats

Biphasic Time Course of the Changes in Aldosterone Biosynthesis Under High-Salt Conditions in Dahl Salt-Sensitive Rats

Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin–angiotensin system in hypertensive rats

Abnormal Downregulation of Caveolin-3 Mediates the Pro-Fibrotic Action of MicroRNA-22 in a Model of Myocardial Infarction

Contact Info

Product

Resources

About