Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis

Abstract

ResultsLoss of CIP accelerates the progress from hypertrophy to heart failure during cardiac remodeling. We and others have previously identified a cardiac ISL1-interacting protein (CIP, also identified and referred to as MLIP [muscle-enriched A-type lamin-interacting protein]) (11,12). CIP is specifically expressed in embryonic and adult mouse myocytes and is highly conserved between mouse and human. We asked whether the expression of this gene is correlated with human cardiomyopathy. Indeed, we found that CIP transcripts were significantly reduced in the hearts of patients with dilated cardiomyopathy ( Figure 1A and Supplemental Table Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte-enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy. As CIP is highly conserved between human and mouse, we evaluated the effects of CIP deficiency on cardiac remodeling in mice. Deletion of the CIP-encoding gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models. Conversely, transgenic and AAV-mediated CIP overexpression prevented pathologic remodeling and preserved cardiac function. CIP deficiency combined with lamin A/C deletion resulted in severe dilated cardiomyopathy and cardiac dysfunction in the absence of stress. Transcriptome analyses of CIP-deficient hearts revealed that the p53-and FOXO1-mediated gene networks related to homeostasis are disturbed upon pressure overload stress. Moreover, FOXO1 overexpression suppressed stress-induced cardiomyocyte hypertrophy in CIP-deficient cardiomyocytes. Our studies identify CIP as a key regulator of cardiomyopathy that has potential as a therapeutic target to attenuate heart failure progression.

Intercalated disc protein Xinβ is required for Hippo-YAP signaling in the heart

“…The research described here complied with all relevant ethical regulations for work with human participants, and patients provided written informed consent prior to tissue collection. Left ventricle (LV) tissues were taken from patients with terminal-stage heart failure indicated for heart transplantation 30 . In brief, the patient's heart was removed at the time of transplantation, and LV tissue was subsequently dissected and snap frozen in liquid nitrogen.…”

Glucose promotes cell growth by suppressing branched-chain amino acid degradation

“…KLF15 cDNA and GFP were separately cloned into ITR-containing AAV plasmid harboring the chicken cardiac TNT promoter to yield constructs pAAV9.cTnT-KLF15 and pAAV9.cTnT-GFP, respectively. AAV was packaged in 293 T cells using AAV9:Rep-Cap and pAd:deltaF6 (Penn Vector Core); then purified and concentrated by gradient centrifugation 61 , 62 . AAV9 titer was determined by Droplet Digital PCR (ddPCR).…”

Long non-coding RNAs link extracellular matrix gene expression to ischemic cardiomyopathy

“…[15][16][17] Additional myocardial samples were obtained from HF patients and controls for RNA extraction and qRT-PCR analysis. 18 For overexpression and knockdown of lncRNAs, CF were isolated from adult or neonatal mouse hearts using a previously described procedure. 19 Details of materials and methods are provided in the Supplementary material online.…”