Abstract Body: Background: Tremendous progress has been made in our understanding of many cardiovascular diseases leading to important new therapeutic approaches. However, their global prevalence remains high, underscoring the need for novel mechanistic insights. Long non-coding RNAs (lncRNAs) are being increasingly recognized as modulators of cardiac pathology. We identified a lncRNA, lncP1, that is highly expressed in cardiomyocytes but significantly downregulated in models of heart failure and cardiac hypertrophy.
Hypothesis: We hypothesize that lncP1 exerts a protective function in cardiomyocytes under stress to mitigate maladaptive cardiac remodeling.
Methods: We generated an AAV9 vector to transiently overexpress lncP1 under the cardiac troponin T promoter in mouse cardiomyocytes (AAV-lncP1), using this same vector to drive GFP (AAV-GFP) as a control. These mice were subjected to transverse aortic constriction (TAC) or sham surgeries at 12 to 16 weeks of age to study their response to chronic pressure overload.
Results: Transient cardiac overexpression of lncP1 via AAV9 attenuated hypertrophic remodeling and improved cardiac function after TAC (n=4-6/group); transcriptomic analyses revealed that lncP1 modulates metabolic and hypertrophic pathways (n=4/group) and several markers were validated via RT-qPCR (n=4-6/group). Subcellular fractionation showed that lncP1 localizes in the cytoplasm and proteomic data suggests a putative interaction of lncP1 with sarcomeric proteins.
Conclusion: Our findings establish lncP1 as a cardiac-enriched lncRNA that protects the heart from pathological remodeling. Future studies will elucidate its cytoplasmic interactions and downstream effectors to help define the specific molecular mechanisms underlying its cardioprotective effects.