Functional, structural and molecular aspects of diastolic heart failure in the diabetic (mRen-2)27 rat

Abstract

These findings indicate that the combination of enhanced tissue renin-angiotensin system and hyperglycaemia lead to the development of diabetic cardiomyopathy. Fibrosis, and myocyte hypertrophy, a prominent feature of this model, may be a consequence of activation of the pro-sclerotic cytokine, transforming growth factor-beta, by the diabetic state.

Insulin supplementation attenuates cancer-induced cardiomyopathy and slows tumor disease progression

“…Diabetic cardiomyopathy is associated with inflammation, fibrosis, and apoptosis, but no such evidence is present in hearts of the two tumor mouse models studied here. Contractile dysfunction in B16F10-TM and C26-TM mice is largely systolic, i.e., reduced fractional shortening, whereas diabetic cardiomyopathy manifests as diastolic dysfunction and impaired ventricular filling due to interstitial collagen accumulation (23). Finally, in diabetic cardiomyopathy, insulin signaling is impaired at the insulin receptor level, a feature not observed in B16F10-TM and C26-TM mice, as evidenced by intact insulin responsiveness, whereby acute and chronic insulin supplementation evoke a normal response of enhanced glucose uptake in vivo and ex vivo.…”

Inhibition of Protein Kinase C–β by Ruboxistaurin Preserves Cardiac Function and Reduces Extracellular Matrix Production in Diabetic Cardiomyopathy

“…6 Indeed, using high fidelity conductance catheters, the gold standard for the assessment of diastolic function, both the early active and later passive components of diastolic relaxation were impaired in this rodent model, despite preserved left ventricular (LV) systolic function. 7 High glucose leads to the induction of a range of intracellular modifications that have been implicated in the patho-genesis of diabetic complications. 8 Among these is the activation of protein kinase C (PKC), a family of intracellular signaling intermediates that induce a myriad of changes in cell function through substrate phosphorylation and as such have been a target of drug discovery programs.…”

“…7 Nucleotide sequences of primers and probes were ␤-myosin heavy chain (MHC) (forward) GTGC-CAAGGGCCTGAATGAG, ␤-MHC (reverse) GCAAAGGCTCCAG-GTCTGA, ␣-MHC (forward) TGTGAAAAGATTAACCGGAGTT-TAAG, ␣-MHC (reverse) TCTGACTTGCGGAGGTATCG. 18 S (forward) TCG AGG CCC TGT AAT TGG AA, (reverse) CCC TCC AAT GGA TCC TCG TT, SERCA-2A (forward) TCT GTC ATT CGG GAG TGG GG, (reverse) GCC CAC ACA GCC AAC GAA AG.…”

“…6 Indeed, using high fidelity conductance catheters, the gold standard for the assessment of diastolic function, both the early active and later passive components of diastolic relaxation were impaired in this rodent model, despite preserved left ventricular (LV) systolic function. 7 High glucose leads to the induction of a range of intracellular modifications that have been implicated in the patho- As in diabetic cardiomyopathy, 6 excess matrix, hypertrophy, and apoptosis are also features of diabetic nephropathy where ruboxistaurin has been shown to attenuate histological injury, functional decline, and the expression of the profibrotic and proapoptotic growth factor, transforming growth factor (TGF)-␤. 10,11 Accordingly, in the present study, we took advantage of the recently validated model of diabetic cardiomyopathy to examine the consequences of diabetes on LV PKC-␤ activity and then to assess the effects of PKC-␤ inhibition on the functional, structural and molecular components of heart failure, focusing in particular, on diastolic disease.…”

“…Animal care was carried out as previously described. 7 All animal studies were approved by the St Vincent's Hospital Animal Ethics Committee in accordance with the Guide for the Care and Use of Laboratory Animals . …”