AAV Mediated Knockdown(KD) of Histidine Rich Calcium Binding Protein (HRC) Showed Deterioration of Cardiac Function after Transverse Aortic Constriction-Induced Heart Failure(TAC-HF)

It has been shown that growth hormone-releasing hormone (GHRH) reduces cardiomyocyte (CM) apoptosis, prevents ischemia/reperfusion injury, and improves cardiac function in ischemic rat hearts. However, it is still not known whether GHRH would be beneficial for life-threatening pathological conditions, like cardiac hypertrophy and heart failure (HF). Thus, we tested the myocardial therapeutic potential of GHRH stimulation in vitro and in vivo, using GHRH or its agonistic analog MR-409. We show that in vitro, GHRH(1-44)NH2 attenuates phenylephrine-induced hypertrophy in H9c2 cardiac cells, adult rat ventricular myocytes, and human induced pluripotent stem cell-derived CMs, decreasing expression of hypertrophic genes and regulating hypertrophic pathways. Underlying mechanisms included blockade of Gq signaling and its downstream components phospholipase Cβ, protein kinase Cε, calcineurin, and phospholamban. The receptor-dependent effects of GHRH also involved activation of Gαs and cAMP/PKA, and inhibition of increase in exchange protein directly activated by cAMP1 (Epac1). In vivo, MR-409 mitigated cardiac hypertrophy in mice subjected to transverse aortic constriction and improved cardiac function. Moreover, CMs isolated from transverse aortic constriction mice treated with MR-409 showed improved contractility and reversal of sarcolemmal structure. Overall, these results identify GHRH as an antihypertrophic regulator, underlying its therapeutic potential for HF, and suggest possible beneficial use of its analogs for treatment of pathological cardiac hypertrophy.

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365 Cardiac contractility modulation with non-excitatory electrical signals normalizes expression of the calcium-binding protein sorcin in dogs with chronic heart failure

European Journal of Heart Failure Supplements ◽

10.1016/s1567-4215(06)80227-4 ◽

2006 ◽

Vol 5 (1) ◽

pp. 80-80

Author(s):

R GUPTA ◽

S MISHRA ◽

S RASTOGI ◽

V ZACA ◽

B ROUSSO ◽

...

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Calcium Binding ◽

Binding Protein ◽

Cardiac Contractility ◽

Calcium Binding Protein ◽

Cardiac Contractility Modulation ◽

Electrical Signals

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Dec1 Deficiency Suppresses Cardiac Perivascular Fibrosis Induced by Transverse Aortic Constriction

International Journal of Molecular Sciences ◽

10.3390/ijms20194967 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4967 ◽

Cited By ~ 2

Author(s):

Le ◽

Sato ◽

Kohsaka ◽

Bhawal ◽

Nakao ◽

...

Keyword(s):

Cardiac Function ◽

Transforming Growth Factor Beta ◽

Calcium Binding ◽

Cardiac Fibrosis ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Transverse Aortic Constriction ◽

Aortic Constriction ◽

Alpha Smooth Muscle Actin ◽

Circadian Expression

Cardiac fibrosis is a major cause of cardiac dysfunction in hypertrophic hearts. Differentiated embryonic chondrocyte gene 1 (Dec1), a basic helix–loop–helix transcription factor, has circadian expression in the heart; however, its role in cardiac diseases remains unknown. Therefore, using Dec1 knock-out (Dec1KO) and wild-type (WT) mice, we evaluated cardiac function and morphology at one and four weeks after transverse aortic constriction (TAC) or sham surgery. We found that Dec1KO mice retained cardiac function until four weeks after TAC. Dec1KO mice also revealed more severely hypertrophic hearts than WT mice at four weeks after TAC, whereas no significant change was observed at one week. An increase in Dec1 expression was found in myocardial and stromal cells of TAC-treated WT mice. In addition, Dec1 circadian expression was disrupted in the heart of TAC-treated WT mice. Cardiac perivascular fibrosis was suppressed in TAC-treated Dec1KO mice, with positive immunostaining of S100 calcium binding protein A4 (S100A4), alpha smooth muscle actin (αSMA), transforming growth factor beta 1 (TGFβ1), phosphorylation of Smad family member 3 (pSmad3), tumor necrosis factor alpha (TNFα), and cyclin-interacting protein 1 (p21). Furthermore, Dec1 expression was increased in myocardial hypertrophy and myocardial infarction of autopsy cases. Taken together, our results indicate that Dec1 deficiency suppresses cardiac fibrosis, preserving cardiac function in hypertrophic hearts. We suggest that Dec1 could be a new therapeutic target in cardiac fibrosis.

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Mildly Increased Renin Expression in the Absence of Kidney Injury in the Murine Transverse Aortic Constriction Model

Frontiers in Pharmacology ◽

10.3389/fphar.2021.614656 ◽

2021 ◽

Vol 12 ◽

Author(s):

Marian Wesseling ◽

Eva Mulder ◽

Maike A. D. Brans ◽

Daniek. M. C. Kapteijn ◽

Marian Bulthuis ◽

...

Keyword(s):

Heart Failure ◽

Renal Function ◽

Cardiac Function ◽

Renal Dysfunction ◽

Systemic Hypertension ◽

Invasive Technique ◽

Transverse Aortic Constriction ◽

Aortic Constriction ◽

Plasma Urea ◽

Progressive Heart Failure

Cardiorenal syndrome type 2 is characterized by kidney failure as a consequence of heart failure that affects >50% of heart failure patients. Murine transverse aortic constriction (TAC) is a heart failure model, where pressure overload is induced on the heart without any systemic hypertension or its consequences. Whether renal function is altered in this model is debated, and if so, at which time post-TAC renal dysfunction starts to contribute to worsening of cardiac function. We therefore studied the effects of progressive heart failure development on kidney function in the absence of chronically elevated systemic blood pressure and renal perfusion pressure. C57BL/6J mice (N = 129) were exposed to TAC using a minimally invasive technique and followed from 3 to 70 days post-TAC. Cardiac function was determined with 3D ultrasound and showed a gradual decrease in stroke volume over time. Renal renin expression and plasma renin concentration increased with progressive heart failure, suggesting hypoperfusion of the kidney. In addition, plasma urea concentration, a surrogate marker for renal dysfunction, was increased post-TAC. However, no structural abnormalities in the kidney, nor albuminuria were present at any time-point post-TAC. Progressive heart failure is associated with increased renin expression, but only mildly affected renal function without inducing structural injury. In combination, these data suggest that heart failure alone does not contribute to kidney dysfunction in mice.

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A novel fibroblast activation inhibitor attenuates left ventricular remodeling and preserves cardiac function in heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00603.2017 ◽

2018 ◽

Vol 315 (3) ◽

pp. H563-H570 ◽

Cited By ~ 4

Author(s):

Jessica M. Bradley ◽

Pablo Spaletra ◽

Zhen Li ◽

Thomas E. Sharp ◽

Traci T. Goodchild ◽

...

Keyword(s):

Heart Failure ◽

Left Ventricular Ejection Fraction ◽

Ejection Fraction ◽

Cardiac Function ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Transverse Aortic Constriction ◽

Aortic Constriction ◽

Ventricular Ejection Fraction ◽

Failing Heart

Cardiac fibroblasts are critical mediators of fibrotic remodeling in the failing heart and transform into myofibroblasts in the presence of profibrotic factors such as transforming growth factor-β. Myocardial fibrosis worsens cardiac function, accelerating the progression to decompensated heart failure (HF). We investigated the effects of a novel inhibitor (NM922; NovoMedix, San Diego, CA) of the conversion of normal fibroblasts to the myofibroblast phenotype in the setting of pressure overload-induced HF. NM922 inhibited fibroblast-to-myofibroblast transformation in vitro via a reduction of activation of the focal adhesion kinase-Akt-p70S6 kinase and STAT3/4E-binding protein 1 pathways as well as via induction of cyclooxygenase-2. NM922 preserved left ventricular ejection fraction ( P < 0.05 vs. vehicle) and significantly attenuated transverse aortic constriction-induced LV dilation and hypertrophy ( P < 0.05 compared with vehicle). NM922 significantly ( P < 0.05) inhibited fibroblast activation, as evidenced by reduced myofibroblast counts per square millimeter of tissue area. Picrosirius red staining demonstrated that NM922 reduced ( P < 0.05) interstitial fibrosis compared with mice that received vehicle. Similarly, NM922 hearts had lower mRNA levels ( P < 0.05) of collagen types I and III, lysyl oxidase, and TNF-α at 16 wk after transverse aortic constriction. Treatment with NM922 after the onset of cardiac hypertrophy and HF resulted in attenuated myocardial collagen formation and adverse remodeling with preservation of left ventricular ejection fraction. Future studies are aimed at further elucidation of the molecular and cellular mechanisms by which this novel antifibrotic agent protects the failing heart. NEW & NOTEWORTHY Our data demonstrated that a novel antifibrotic agent, NM922, blocks the activation of fibroblasts, reduces the formation of cardiac fibrosis, and preserves cardiac function in a murine model of heart failure with reduced ejection fraction.

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Abstract 214: Septin4 Deletion Prevents Hypertrophy to Heart Failure Transition After Transverse Aortic Constriction

Circulation Research ◽

10.1161/res.127.suppl_1.214 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Dogacan Yucel ◽

Jop H Van Berlo ◽

Preethy Parthiban

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Cardiac Function ◽

Ventricular Remodeling ◽

Pressure Overload ◽

Small Gtpase ◽

Calcium Handling ◽

Future Research ◽

Transverse Aortic Constriction ◽

Aortic Constriction

In response to cardiac injury or increased workload, the mammalian heart undergoes ventricular remodeling to maintain cardiac function. Initally, these changes are compensatory, although ultimately, they can lead to death of cardiomyocytes, ventricular dilation, and progression to heart failure. It is critical to understand the underlying mechanisms that regulate this transition, since it could identify new therapeutic targets. The role of the small GTPase Septin4 in the heart, and in regulating cardiac stress response is unknown. Previous research has implicated Septin 4 in regulation of Store Operated Calcium entry, as well as cell death regulation through a splice isoform (ARTS). We performed cardiac pressure overload in wild type controls and Septin 4 knockout (-/-) mice. Importantly, we did not detect differences in cardiac hypertrophy or function at baseline (57% ejection fraction in both groups). Four weeks following transverse aortic constriction (TAC), Septin4-/- mice showed improved cardiac function with higher ejection fraction (51%) compared to controls (40%), while the level of hypertrophy was similar. Furthermore, we detected reduced cleaved caspase-3 staining after TAC in Septin4-/- mice, due to inhibition of cardiomyocyte apoptosis in Septin4 -/- mice. Mechanistically, we detected increases in protein expression of both total and phosphorylated phospholamban and CaMKII in Septin4-/- mice, suggesting alterations in Calcium handling, and indicating compensatory signaling pathways were still active in Septin4-/- mice, while control mice were transitioning to heart failure. In conclusion, genetic deletion of Septin4 prevented cardiomyocyte death and protected mice from heart failure following cardiac pressure overload. Future research will focus on regulation of calcium handling in Septin4-/- mice to determine the exact mechanisms through which Septin4 plays a detrimental role in cardiac remodeling.

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