Signal transducer and activator of transcription-3 (STAT-3) mediated signalling in relation to upregulated collagen expression in fibroblasts is well defined during cardiac hypertrophy. Recent findings from our laboratory have identified Heat shock protein 90 (Hsp90) as a critical modulator of fibrotic signalling in cardiac fibroblasts in this disease milieu. The present study was therefore intended to analyze the role of Hsp90 in the STAT-3 mediated collagen upregulation process. Our data revealed a significant difference between in vivo and in vitro results pointing to a possible involvement of myocyte-fibroblast crosstalk in this process. Cardiomyocyte targeted knockdown of Hsp90 in renal artery ligated rats (Rattus norvegicus) showed downregulated collagen synthesis. Furthermore, cardiac fibroblasts conditioned with Hsp90 inhibited hypertrophied myocyte supernatant pointed towards cardiomyocytes' role in regulation of collagen expression in fibroblasts during hypertrophy. Our study also revealed a novel signalling mechanism where myocyte derived Hsp90 not only orchestrates p65 mediated Interleukin-6 (IL-6) synthesis but also its release in exosomal vesicles. Such myocyte derived exosomes along with myocyte secreted IL-6 are responsible in unison for the biphasic activation of STAT-3 signalling in cardiac fibroblasts that culminates in excess collagen synthesis leading to severely compromised cardiac function during cardiac hypertrophy.

Pathological cardiac damage during heart failure is associated with cell death and damage associated molecular patterns (DAMPs) release which triggers a viscous cycle of sterile inflammation to mediate maladaptive cardiac tissue remodelling during the progression to heart failure. DAMPs like cytokines, chemokines, and nuclear or mitochondrial genomic fragments are released in the pathological myocardium. Interestingly, circulating or cytosolic DNA fragments can play a role in the disease by interaction with nucleic acid sensors expressed in cardiomyocyte and non-myocyte neighbouring cells. The circulating cell free DNA (cfDNA) fragments have been clinically reported as markers for various diseases including cardiovascular pathophysiology. Such cfDNA within the DAMP pool can mediate intra- and inter-cellular signalling cascade to upregulate transcriptional expression of inflammatory mediators and trigger oxidative stress within cells. The cellular role of such genomic equivalents varying with chronic or acute stress might be correlated with the cell death forms encountered in myocardium during disease progression. Thus, cfDNA can be phenotypically correlated as a critical player towards upregulation of pathological processes like interstitial fibrosis, cardiomyocyte contractile dysfunction and cell death. Herein, we review the association of cfDNA with heart failure and analyse their potential usage as novel and effective therapeutic targets towards augmentation of cardiac function.