Targeting Excitation-Transcription Coupling for Managing Hypertensive Cardiomyopathy

Hypertensive cardiomyopathy or pathophysiological changes in myocardial structure and function caused by hypertension is a growing clinical problem due to the ageing population and a lack of curative therapies. The onset of the disease is often clinically silent, progressing over time to therapy-resistant symptomatic forms. Understanding molecular processes driving hypertension-induced early cardiac remodeling may improve diagnosis and treatment options.

Recent evidence positions changes in Ca²⁺ cycling as an early promoter of cardiac remodeling via Ca²⁺-mediated regulation of transcription. The enzyme Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) has a central role in this process, as it can translate fine changes in Ca²⁺ fluxes into altered gene expression.

This project aims to provide a complete characterization of the CaMKII-mediated transcription in hypertensive cardiomyopathy at the molecular, cellular and whole organism level. We will follow the hypothesis that (1) changes in Ca²⁺-mediated transcriptional activity are causally involved in the initiation and progression of hypertensive cardiomyopathy and (2) heart-specific targeting of the altered transcription via inhalation of CaMKII inhibitory peptide-loaded nanoparticles can halt disease progression or even delay its manifestation.

Through our multi-disciplinary and translational approach we will acquire better understanding of cardiac remodeling and provide necessary evidence to support future clinical studies employing peptide-loaded nanocarriers as a remedy for treating hypertensive cardiomyopathy.