International Journal of Molecular Medical Science, 2025, Vol.15, No.1, 42-53 http://medscipublisher.com/index.php/ijmms 45 mutation leads to a characteristic pattern of hypertrophy and a higher prevalence of atrial fibrillation among affected individuals (Gruver et al., 1999). Mutations in structural genes like MYH7 and ACTC1 can alter myocardial contractile function by affecting the assembly and function of the sarcomere, the fundamental unit of muscle contraction. These mutations can lead to disorganized sarcomere structure, impaired contractility, and increased myocardial stiffness, contributing to hypertrophy and fibrosis. The resultant changes in myocardial architecture and function can predispose individuals to arrhythmias and heart failure. 3.3 Blood pressure regulation gene mutations Mutations in genes involved in the Renin-Angiotensin System (RAS), such as AGT (angiotensinogen) and REN (renin), can significantly impact blood pressure regulation. These mutations can lead to dysregulation of the RAS, resulting in altered angiotensin II levels, which in turn can cause hypertension and contribute to hypertensive heart disease. Elevated angiotensin II levels can promote vasoconstriction, sodium retention, and increased blood pressure, all of which are risk factors for developing hypertensive heart disease. The sympathetic nervous system plays a crucial role in regulating blood pressure, and its dysregulation can lead to hypertension. Mutations in genes that affect sympathetic nervous system activity can lead to increased sympathetic tone, elevated heart rate, and vasoconstriction, all of which contribute to hypertension. These molecular mechanisms can exacerbate the effects of RAS dysregulation, further increasing the risk of hypertensive heart disease. 3.4 Epigenetic regulatory gene mutations Epigenetic regulatory genes such as DNMT3A(DNA methyltransferase 3 alpha) and HDAC(histone deacetylase) play critical roles in cardiovascular health by modulating gene expression through DNA methylation and histone modification. Mutations in these genes can lead to aberrant epigenetic regulation, contributing to the development of cardiovascular diseases. For instance, altered DNA methylation patterns can affect the expression of genes involved in cardiac function and structure, leading to conditions such as hypertrophy and fibrosis. Similarly, dysregulation of histone deacetylation can impact chromatin structure and gene expression, further contributing to cardiovascular pathology (Mason, 2024). 4 Mechanisms Linking FHH-Related Gene Mutations to Disease 4.1 How gene mutations affect myocardial remodeling Gene mutations associated with Familial Hypertensive Heart disease (FHH) significantly impact myocardial remodeling. Mutations in sarcomeric proteins, such as those found in the cardiac troponin T (cTnT) and beta-Myosin Heavy chain (MYH7) genes, alter the structural and functional properties of cardiomyocytes. These mutations can lead to Hypertrophic Cardiomyopathy (HCM), characterized by increased myocardial mass and altered contractile function (Bundgaard et al., 1999; Nicol et al., 2000; Manning et al., 2012). For instance, mutations in the TNT1 domain of cTnT affect the flexibility and cooperativity of calcium activation in the thin filament, which in turn influences myocardial contractility and hypertrophy (Manning et al., 2012). Additionally, MYH7 mutations in the ATP-binding region disrupt the coupling between ATP hydrolysis and mechanical energy transition, contributing to myocardial hypertrophy (Bundgaard et al., 1999). 4.2 Genetic regulation of vascular function Mutations in genes regulating ion transport and vascular function play a crucial role in FHH. For example, mutations in the CUL3 and KLHL3 genes, which are part of the E3-ubiquitin-ligase complex, affect the degradation of target proteins such as WNK1 and WNK4 kinases. These kinases are involved in ion transport regulation in the kidney, impacting blood pressure and vascular function (Louis-dit-Picard et al., 2012; Hl et al., 2015). The CUL3-delta-exon9 mutation, in particular, leads to severe phenotypes with early diagnosis and significant vascular damage, suggesting a direct link between these genetic mutations and vascular dysfunction (Hl et al., 2015). Furthermore, KLHL3 mutations impair ion transport in the distal nephron, contributing to hypertension and altered vascular homeostasis (Louis-dit-Picard et al., 2012).
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