Modified desmin pre-amyloid oligomers are increased in experimental heart failure

Objectives: Heart Failure (HF) is the major cause of hospitalization in the US but the molecular mechanisms underlying its development are unclear to date. The increased formation of preamyloid oligomers (PAOs), similar to those observed in Alzheimer's disease, have been reported in several different models of HF. We first reported that the induction of desmin phosphorylation at serines (S) 27 and 31 associate with increased cardiac PAOs deposition in experimental, non-genetic HF. We now show that modified desmin is a likely candidate for the seed initiating the nucleation of toxic PAOs in the heart and isolated cardiac cells. Materials and methods: We subjected mice to transverse aortic constriction (TAC) for 4 weeks (FS% = 29.3 ± 2.6, P = 0.0001) and transduced neonatal rat ventricular myocytes (NRVMs) using lentiviral vectors carrying alanine (A) or phospho-mimetic aspartate (D) desmin double mutants at S27 and S31, fused with GFP. We analyzed the formation of PAOs in cardiac protein extracts by western blot analysis combined with infrared detection, which enabled the contemporary measurement of PAOs and desmin. We also monitored the effects of phospho-mimetic desmin expression in NRVMs by live imaging. Results: Co-staining for both desmin and PAOs in TAC mice and NRVMs confirmed the co-migration (by molecular weight) of PAOs with modified desmin, along with their increase in experimental HF (≈3-fold, P = 0.023 and ≈ 2-fold, P = 0.038, respectively). Cells expressing the doubly phospho-mimetic mutant, which we believe is the physiological form, displayed a “healthier” phenotype as docu- mented by the number of contracting cells (P = 0.041) and localiza- tion of GFP desmin at the Z-bands (P = 0.0027). On the contrary the expression of mono-phosphomimetic mutant (S27A, S31D) induced increased desmin aggregation (P = 0.0014). Conclusions: These data strongly suggest that modified desmin constitutes the seed initiating the formation of cardiac PAOs in non- genetic HF. The increased levels of toxic desmin PAOs in the heart could, therefore, represent a novel mechanism of organ dysfunction in HF, in the absence of genetic mutations.