Targeting caveolin-3 for the treatment of diabetic cardiomyopathy

Murfitt, Lucy; Whiteley, Gareth; Iqbal, Mohammad M; Kitmitto, Ashraf

doi:10.1016/j.pharmthera.2015.03.002

Cited by 23 publications

(28 citation statements)

References 330 publications

(330 reference statements)

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“…4a). It was reported that increased phosphorylation of Akt at Ser473 and eNOS at Ser1177 may improve NO release and cardiac function [16, 50]. Consistently, miR-21 increased the expression of p-Akt(Ser473) and p-eNOS(Ser1177) in db/db mice (Fig.…”

Section: Resultssupporting

confidence: 63%

MiR-21 protected against diabetic cardiomyopathy induced diastolic dysfunction by targeting gelsolin

Dai

Fan

et al. 2018

Cardiovasc Diabetol

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BackgroundDiabetes is a leading cause of mortality and morbidity across the world. Over 50% of deaths among diabetic patients are caused by cardiovascular diseases. Cardiac diastolic dysfunction is one of the key early signs of diabetic cardiomyopathy, which often occurs before systolic dysfunction. However, no drug is currently licensed for its treatment.MethodsType 9 adeno-associated virus combined with cardiac Troponin T promoter were employed to manipulate miR-21 expression in the leptin receptor-deficient (db/db) mice. Cardiac structure and functions were measured by echocardiography and hemodynamic examinations. Primary cardiomyocytes and cardiomyocyte cell lines were used to perform gain/loss-of-function assays in vitro.ResultsWe observed a significant reduction of miR-21 in the diastolic dysfunctional heart of db/db mice. Remarkably, delivery of miR-21 efficiently protected against the early impairment in cardiac diastolic dysfunction, represented by decreased ROS production, increased bioavailable NO and relieved diabetes-induced cardiomyocyte hypertrophy in db/db mice. Through bioinformatic analysis and Ago2 co-immunoprecipitation, we identified that miR-21 directly targeted gelsolin, a member of the actin-binding proteins, which acted as a transcriptional cofactor in signal transduction. Moreover, down-regulation of gelsolin by siRNA also attenuated the early phase of diabetic cardiomyopathy.ConclusionOur findings reveal a new role of miR-21 in attenuating diabetic cardiomyopathy by targeting gelsolin, and provide a molecular basis for developing a miRNA-based therapy against diabetic cardiomyopathy.Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0767-z) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 63%

MiR-21 protected against diabetic cardiomyopathy induced diastolic dysfunction by targeting gelsolin

Dai

Fan

et al. 2018

Cardiovasc Diabetol

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“…See Table 1 for patient data. There was no difference in age between control and statin groups, and those with a diagnosis of diabetes were excluded from the study (as diabetes has a myriad of cardiac effects including changes in Cav expression) (Murfitt et al, 2015). Key changes in protein expression/phosphorylation with statin treatment in the rat were mirrored in human samples, although possibly because of the small sample size these did not attain statistical significance.…”

Section: Resultsmentioning

confidence: 99%

Simvastatin Promotes Cardiac Myocyte Relaxation in Association with Phosphorylation of Troponin I

et al. 2017

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The number of people taking statins is set to increase across the globe due to recent changes in prescription guidelines. For example, half the US population over 40 is now eligible for these drugs, whether they have high serum cholesterol or not. With such development in policy comes a stronger need for understanding statins’ myriad of effects. Surprisingly little is known about possible direct actions of statins on cardiac myocytes, although claims of a direct myocardial toxicity have been made. Here, we determine the impact of simvastatin administration (40 mg/kg/day) for 2 weeks in normocholesterolemic rats on cardiac myocyte contractile function and identify an underlying mechanism. Under basal conditions, statin treatment increased the time to half (t0.5) relaxation without any effect on the magnitude of shortening, or the magnitude/kinetics of the [Ca2+]i transient. Enhanced myocyte lusitropy could be explained by a corresponding increase in phosphorylation of troponin I (TnI) at Ser23,24. Statin treatment increased expression of eNOS and Ser1177 phosphorylated eNOS, decreased expression of the NOS-inhibitory proteins caveolins 1 and 3, and increased (P = 0.06) NO metabolites, consistent with enhanced NO production. It is well-established that NO stimulates protein kinase G, one of the effectors of TnI phosphorylation at Ser23,24. Trends for parallel changes in phospho-TnI, phospho-eNOS and caveolin 1 expression were seen in atrial muscle from patients taking statins. Our data are consistent with a mechanism whereby chronic statin treatment enhances TnI phosphorylation and myocyte lusitropy through increased NO bioavailability. We see no evidence of impaired function with statin treatment; the changes we document at the level of the cardiac myocyte should facilitate diastolic filling and cardiac performance.

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“…, Murfitt et al . ). Caveolin‐3 null mice show cardiac hypertrophy, reduced fractional shortening, perivascular fibrosis, myocyte hypertrophy and cellular infiltration (Cohen et al .…”

Section: Direct Effects Of Glp‐1 On the Cardiovascular Systemmentioning

confidence: 97%

“…, Murfitt et al . ). The cardioprotective effects of GLP‐1 against reactive oxygen species may also be dependent on exchange protein directly activated by cAMP (Epac).…”

Section: Direct Effects Of Glp‐1 On the Cardiovascular Systemmentioning

confidence: 97%

“…Recent research in caveolin-3 null mice suggests that cardioprotective effects of GLP-1 against myocardial ischaemia/reperfusion injury are mediated, at least in part, by caveolin-3 (Hamaguchi et al 2015). Caveolin-3, responsible for caveolae formation in cardiomyocytes, regulates numerous processes including insulin signalling, glucose uptake, stabilization and trafficking of cardiac ion channels to the plasma membrane, interactions with proteins involved in excita-tion-contraction coupling, which are all very important for cardiac structure and function (Cohen et al 2004, Murfitt et al 2015. Caveolin-3 null mice show cardiac hypertrophy, reduced fractional shortening, perivascular fibrosis, myocyte hypertrophy and cellular infiltration (Cohen et al 2004, Murfitt et al 2015.…”

Section: Effects Of Glp-1 On the Cardiovascular System: The Classicalmentioning

confidence: 99%

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Mechanisms for the cardiovascular effects of glucagon-like peptide-1

Poudyal

2015

Acta Physiol

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Over the past three decades, at least 10 hormones secreted by the enteroendocrine cells have been discovered, which directly affect the cardiovascular system through their innate receptors expressed in the heart and blood vessels or through a neural mechanism. Glucagon-like peptide-1 (GLP-1), an important incretin, is perhaps best studied of these gut-derived hormones with important cardiovascular effects. In this review, I have discussed the mechanism of GLP-1 release from the enteroendocrine L-cells and its physiological effects on the cardiovascular system. Current evidence suggests that GLP-1 has positive inotropic and chronotropic effects on the heart and may be important in preserving left ventricular structure and function by direct and indirect mechanisms. The direct effects of GLP-1 in the heart may be mediated through GLP-1R expressed in atria as well as arteries and arterioles in the left ventricle and mainly involve in the activation of multiple pro-survival kinases and enhanced energy utilization. There is also good evidence to support the involvement of a second, yet to be identified, GLP-1 receptor. Further, GLP-1(9-36)amide, which was previously thought to be the inactive metabolite of the active GLP-1(7-36)amide, may also have direct cardioprotective effects. GLP-1's action on GLP-1R expressed in the central nervous system, kidney, vasculature and the pancreas may indirectly contribute to its cardioprotective effects.

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Targeting caveolin-3 for the treatment of diabetic cardiomyopathy

Cited by 23 publications

References 330 publications

MiR-21 protected against diabetic cardiomyopathy induced diastolic dysfunction by targeting gelsolin

MiR-21 protected against diabetic cardiomyopathy induced diastolic dysfunction by targeting gelsolin

Simvastatin Promotes Cardiac Myocyte Relaxation in Association with Phosphorylation of Troponin I

Mechanisms for the cardiovascular effects of glucagon-like peptide-1

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