Methods and results: Diabetes was induced by administration of
streptozotocin (55 mg/kg, i.p.) in male Wistar rats. After 4 weeks, diabetic rats were subjected to either
thiorphan (0.1 mg/kg/day, p.o.) or
telmisartan (10 mg/kg/day, p.o.) monotherapy, or their combination, for a period of 4 weeks. Metabolic and morphometric alterations, failing ventricular functions, and diminished baroreflex indicated development of diabetic cardiac complications. Apart from morphometric alterations, all pathological consequences were prevented by
telmisartan and
thiorphan combination
therapy. Diabetic rats exhibited significant modulation of the
natriuretic peptide system, a key haemodynamic regulator; this was normalized by combination
therapy. Histopathological studies showed augmented myocardial
fibrosis, demonstrated by increased % PSR-positive area, with combination
therapy giving the best improvement in these indices. More importantly, the combination of
thiorphan and
telmisartan was superior in attenuating inflammatory (NF-κB/MCP-1), profibrotic (TGF-β/Smad7) and apoptotic (PARP/
Caspase-3) cascades compared to respective monotherapies when treating rats with
diabetic cardiomyopathy. In addition, diabetic heart
chromatin was in a state of active transcription, indicated by increased
histone acetylation (H2AK5Ac, H2BK5Ac, H3K9Ac, and H4K8Ac) and
histone acetyltransferase (PCAF and Ac-CBP) levels. Interestingly, combination treatment was sufficiently potent to normalize these alterations.
Conclusion: The protective effect of novel ARB and NEPi combination against
diabetic cardiomyopathy can be attributed to inhibition of inflammatory, profibrotic, and apoptotic cascades. Moreover, reversal of
histone acetylation assists its protective effect.